Tachykinin antagonists

ABSTRACT

The invention concerns tachykinin antagonists. The compounds are neopeptides which have utility in treating disorders mediated by tachykinins. Such disorders are respiratory, inflammatory, gastrointestinal, ophthalmic, allergies, pain, vascular, diseases of the central nervous system, and migraine. Methods of preparing compounds and novel intermediates are also included. The compounds are expected to be especially useful in asthma and rheumatoid arthritis.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 08/727,067 filedOct. 8, 1996 which application is now U.S. Pat. No. 5,716,979, which isa division of Ser. No. 08/344,064 filed Nov. 29, 1994, now U.S. Pat. No.5,594,022 and a continuation-in-part of U.S. patent application Ser. No.08/097,264, filed Jul. 23, 1993 now abandoned; which is acontinuation-in-part of U.S. application Ser. No. 07/930,252, filed Aug.13, 1992, now abandoned.

BACKGROUND OF THE INVENTION

Over the last decade, major advances have been made in the understandingof the biology of the mammalian tachykinin neuropeptides. It is now wellestablished that substance-P (1), neurokinin A (NKA) (2), and neurokininB (NKB) (3), all of which share a common C-terminal sequencePhe-X-Gly-Leu-Met-NH₂, (Nakanishi S, Physiol Rev 1987;67:117), arewidely distributed throughout the periphery and central nervous system(CNS) where they appear to interact with at least three receptor typesreferred to as NK₁, NK₂, and NK₃, (Guard S, et al., Neurosci Int1991;18:149). Substance-P displays highest affinity for NK₁ receptors,whereas NKA and NKB bind preferentially to NK₂ and NK₃ receptors,respectively. Recently, all three receptors have been cloned andsequenced and shown to be members of the G-protein-linked "super family"of receptors (Nakanishi S, Annu Rev Neurosci 1991;14:123). A wealth ofevidence supports the involvement of tachykinin neuropeptides in avariety of biological activities including pain transmission,vasodilation, smooth muscle contraction, bronchoconstriction, activationof the immune system (inflammatory pain), and neurogenic inflammation(Pernow B, Pharmacol Rev 1983;35:85). However, to date, a detailedunderstanding of the physiological roles of tachykinin neuropeptides hasbeen severely hampered by a lack of selective, high affinity,metabolically stable tachykinin receptor antagonists that possess bothgood bioavailability and CNS penetration. Although several tachykininreceptor antagonists have been described (Tomczuk B E, et al., CurrentOpinions in Therapeutic Patents 1991;1:197), most have been developedthrough the modification and/or deletion of one or more of the aminoacids that comprise the endogenous mammalian tachykinins such that theresulting molecules are still peptides that possess poor pharmacokineticproperties and limited in vivo activities.

However, since 1991, a number of high-affinity nonpeptide antagonistshave been reported. Snider R M, et al, (Science 1991;251:435), andGarret C, et al, (Proc Natl Acad Sci 1991;88:10208), described CP-96,345and RP 67580, respectively, as antagonists at the NK₁ receptor, whileAdvenier C, et al., (Brit J Pharmacol 1992;105:78), presented data on SR48969 showing its high affinity and selectivity for NK₂ receptors. It isof interest that most of the nonpeptide tachykinin receptor antagonistsdescribed to date arose, either directly or indirectly, out of thescreening of large compound collections using a robust radioligandbinding assay as the primary screen. Recently, FK 888, a "dipeptide"with high affinity for the NK₁ receptor was described (Fujii J, et al.,Neuropeptide 1992;22:24).

International Publication Numbers WO 93/01169, WO 93/01165, and WO93/001160 cover certain nonpeptide tachykinin receptor antagonists.

Substance-P is widely distributed throughout the periphery and centralnervous system. It is believed to mediate a variety of biologicalactions, via an interaction with three receptor types referred to asNK₁, NK₂, and NK₃, including smooth muscle contraction, paintransmission, neuronal excitation, secretion of saliva, angiogenesis,broncho-constriction, activation of the immune system and neurogenicinflammation.

Accordingly, compounds capable of antagonizing the effects ofsubstance-P at NK₁ receptors will be useful in treating or preventing avariety of brain disorders including pain, anxiety, panic, depression,schizophrenia, neuralgia, and addiction disorders; inflammatory diseasessuch as arthritis, asthma, and psoriasis; gastrointestinal disordersincluding colitis, Crohn's disease, irritable bowel syndrome, andsatiety; allergic responses such as eczema and rhinitis; vasculardisorders such as angina and migraine; neuropathological disordersincluding Parkinson's disease, multiple sclerosis, and Alzheimer'sdisease; and ophthalmic diseases including scleroderma.

The compounds of the invention, NK₁ receptor antagonists, are useful asanti-angiogenic agents for the treatment of conditions associated withaberrant neovascularization such as rheumatoid arthritis,atherosclerosis, and tumor cell growth. They will also be useful asagents for imaging NK₁ receptors in vivo in conditions such asulcerative colitis and Crohn's disease.

SUMMARY OF THE INVENTION

The invention covers tachykinin antagonists. The compounds arenonpeptides which have proved to be highly selective and functionaltachykinin antagonists.

These compounds are unique in the alkylation/substitution pattern alongtheir back bone.

Compounds of the invention are those of formula ##STR1## or apharmaceutically acceptable salt thereof wherein R is phenyl,

pyridine,

thiophene,

furan,

naphthalene,

indole,

benzofuran, or

benzothiophene each unsubstituted,

mono-, di-, or trisubstituted by

alkyl,

hydroxy,

alkoxy,

NO₂,

halogen,

NH₂, or

CF₃ ;

R¹ and R² are each independently hydrogen or alkyl of from 1 to 4 atoms;

R and R², when joined by a bond, can form a ring;

X is ##STR2## wherein R¹¹ is hydrogen or alkyl of from 1 to 3 carbonatoms; R³ is hydrogen or (CH₂)_(m) R¹³ where m is an integer of from 1to 6 and R¹³ is H, CN, NH₂, N(CH₃)₂, or NHCOCH₃ ;

n is an integer of from 1 to 2;

R⁸ is phenyl,

pyridine,

thiophene,

furan,

naphthalene,

indole,

benzofuran, or

benzothiophene each unsubstituted, or

mono-, di-, or trisubstituted by

alkyl,

hydroxy,

alkoxy,

NO₂,

halogen,

NH₂, or

CF₃ ;

Y is ##STR3## wherein R⁴ is hydrogen or alkyl of from 1 to 3 carbonatoms, --CO₂ --,

--COCH₂ --,

--CH₂ O--,

--CH₂ NH--,

--CH═CH--,

--CH₂ CH₂ --,

--CHOHCH₂ --, ##STR4## wherein B is nitrogen, CH, CH₂, oxygen, orsulfur, D is nitrogen, oxygen, or sulfur, E is nitrogen or CH, CH₂, p isan integer of from 3 to 4, and the dotted line indicates a double orsingle bond;

R⁵ and R⁷ are each independently hydrogen or alkyl of from 1 to 4 carbonatoms;

q is an integer of from 0 to 1; and

R⁶ is phenyl,

pyridine,

thiophene,

furan,

naphthalene,

indole,

benzofuran, or

benzothiophene each unsubstituted, or

mono-, di-, or trisubstituted by

alkyl,

hydroxy,

alkoxy,

NO₂,

halogen,

NH₂, or

CF₃ ;

straight alkyl of from 1 to 8 carbons, branched alkyl of from 3 to 8carbons, cycloalkyl of from 5 to 8 carbons, or heterocycloalkyl.

Other cyclic derivatives of Formula I are contemplated such as wouldoccur to one skilled in the art.

Prodrugs of the above are also contemplated such as would occur to oneskilled in the art, see Bundgaard, et al., Acta Pharm Suec,1987;24:233-246. For example, where a suitable moiety has been attachedto the linker X or Y or the indole N.

Preferred compounds of the invention are those of Formula I abovewherein

R is pyridine,

thiophene,

furan,

naphthalene,

indole,

benzofuran, or

benzothiophene each unsubstituted,

mono-, di-, or trisubstituted by

alkyl,

hydroxy,

alkoxy,

NO₂,

halogen,

NH₂, or

CF₃ ;

R¹ and R² are each independently hydrogen or alkyl of from 1 to 4 atoms;

R and R², when joined by a bond, can form a ring;

X is ##STR5## wherein R¹¹ is hydrogen or alkyl of from 1 to 3 carbonatoms; R³ is hydrogen or (CH₂)_(m) R¹³ where m is an integer of from 1to 6 and R¹³ is H, CN, NH₂, N(CH₃)₂, or NHCOCH₃ ;

n is an integer of from 1 to 2;

R⁸ is phenyl,

pyridine,

thiophene,

furan,

naphthalene,

indole,

benzofuran, or

benzothiophene each unsubstituted, or

mono-, di-, or trisubstituted by

alkyl,

hydroxy,

alkoxy,

NO₂,

halogen,

NH₂, or

CF₃ ;

Y is ##STR6## wherein R⁴ is hydrogen or alkyl of from 1 to 3 carbonatoms, --CO₂ --,

--COCH₂ --,

--CH₂ O--,

--CH₂ NH--,

--CH═CH--,

--CH₂ CH₂ --,

--CHOHCH₂ --, ##STR7## wherein B is nitrogen, CH, CH₂, oxygen, orsulfur, D is nitrogen, oxygen, or sulfur, E is nitrogen, CH, CH₂, p isan integer of from 3 to 4, and the dotted line indicates a double orsingle bond;

R⁵ and R⁷ are each independently hydrogen or alkyl of from 1 to 4 carbonatoms;

q is an integer of from 0 to 1; and

R⁶ is phenyl,

pyridine,

thiophene,

furan,

naphthalene,

indole,

benzofuran, or

benzothiophene each unsubstituted, or

mono-, di-, or trisubstituted by

alkyl,

hydroxy,

alkoxy,

NO₂,

halogen,

NH₂, or

CF₃ ;

straight alkyl of from 1 to 8 carbons, branched alkyl of from 3 to 8carbons, cycloalkyl of from 5 to 8 carbons, or heterocycloalkyl;

More preferred compounds of the invention are those of Formula I abovewherein

R is phenyl

pyridyl,

thiophene,

furan,

naphthalene,

indole each unsubstituted, or

mono- or disubstituted by alkyl of 1 to 3 carbons, methoxy, ethoxy,chlorine, fluorine, NH₂, or CF₃ ;

R¹ and R² are each independently selected from hydrogen and methyl;

X is ##STR8## wherein R¹¹ is hydrogen or methyl; R³ is hydrogen or(CH₂)_(m) R¹³ where m is an integer of from 1 to 6 and R¹³ is H, CN,NH₂, N(CH₃)₂, or NHCOCH₃ ;

n is 1;

R⁸ is phenyl,

naphthyl,

indole, or

benzothiophene;

Y is ##STR9## wherein R⁴ is hydrogen or methyl --CO₂ --, ##STR10##wherein B is CH, CH₂, D is sulfur, and E is CH, CH₂ ; R⁵ and R⁷ are eachindependently hydrogen or methyl;

q is an integer of from 0 to 1, and

R⁶ is phenyl, substituted phenyl, or cyclohexyl.

Still more preferred compounds of the invention are those of Formula Iwherein

R is phenyl

thiophene,

furan,

each unsubstituted, or mono- or disubstituted by alkyl of 1 to 3carbons, methoxy, ethoxy, chlorine, fluorine, NH₂, or CF₃ ;

R¹ and R² are each independently hydrogen or methyl;

X is ##STR11## R³ is hydrogen or methyl; n is 1;

R⁸ is indole;

Y is ##STR12## R⁵ and R⁷ are each independently hydrogen or methyl; q is1;

R⁶ is phenyl, substituted phenyl, or cyclohexyl.

Still more especially preferred compounds of the invention are:

phenylmethyl (S)- 1-(1H-indol-3-ylmethyl)-2-methyl(phenylmethyl)amino!-2-oxoethyl!carbamate;

phenylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate;

phenylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate;

phenylmethyl S-(R*,R*)!- 1-(1H-indol-3-ylmethyl)-2-oxo-2-(1-phenylethyl)amino!ethyl!methyl!carbamate;

phenylmethyl S-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-2-oxo-2-(1-phenylethyl)amino!ethyl!methylcarbamate;

(4-chlorophenyl)methyl (S)- 1-(1H-indole-3-ylmethyl)-2-oxo-2-(phenylmethyl)amino!ethyl!methyl!carbamate;

(4-methoxyphenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate;

(4-chlorophenyl)methyl R-(R*,S*)!- 1-(1H-indol-ethyl!carbamate;

(4-methylphenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate;

phenylmethyl (S)- 1-(1H-indol-3-ylmethyl)-2-methyl(phenylmethyl)amino!-2-oxoethyl!carbamate;

phenylmethyl (S)- 2-(4-chlorophenyl)methyl!-amino!1-(1H-indol-3-ylmethyl)-2-oxoethyl!-methylcarbamate;

phenylmethyl (S)- 1-(1H-indol-3-ylmethyl)-2-oxo-2-4-(trifluoromethyl)phenyl!methyl!amino!ethyl!methylcarbamate;

methyl N- (phenylmethoxy)carbonyl!-,3,5-bis(trifluoromethyl)phenyl!-L-tryptophan;

phenylmethyl 1-(1H-indol-3-ylmethyl)-1-methyl-2-1-(4-methylphenyl)ethyl!amino!-2-oxoethyl!carbamate;

phenylmethyl R-(R*,R*)!- 2-(1-cyclohexylethyl)amino!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl!carbamate;

phenylmethyl 2- 1-3,5-bis(trifluoromethyl)phenyl!ethyl!amino!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl!carbamate;

phenylmethyl (R,RS)- 1-(1H-indol-3-ylmethyl)-2-1-(4-methoxyphenyl)ethyl!amino!-1-methyl-2-oxoethyl!carbamate;

4-pyridinylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!carbamate;

3-thienylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate;

2-thienylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate;

2,3-dihydro-1H-inden-3-yl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

1-naphthalenylmethyl R- (R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

2,3-dihydro-1H-inden-2-yl 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

(2-fluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

3-furanylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

2-furanylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

(3-fluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

(2,3-difluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

(4-fluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

(2,4-difluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

(2,5-difluorophenyl)methyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!ethyl!carbamate;

phenylmethyl R-(R*,S*)! and S-(R*,R*)!-1-(1H-indazol-3-ylmethyl)-2-oxo-2- (1-phenylethyl)amino!ethyl!carbamate;

phenylmethyl R-(R*,S*)! and S-(R*,R*)!- 1-(5-fluoro-1H-indol-3-yl)methyl!-2-oxo-2-(1-phenylethyl)amino!ethyl)carbamate;

phenylmethyl 1-(1-methyl-1H-indol-3-ylmethyl)-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate;

phenylmethyl R-(R*,S*)!- 1-(2-naphthalenylmethyl)-2-oxo-2-(1-phenylmethyl)amino!ethyl!carbamate;

1-phenylethyl (S)-N- (phenylmethoxy)carbonyl!-DL-tryptophan, (S)-;

phenylmethyl 1-(benzo b!thien-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate;

carbamic acid, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!-, 2-benzofuranylmethyl ester, R-(R*,S*)!;

carbamic acid, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!-, benzo b!thien-2-ylmethyl ester,R-(R*,S*)!;

(2-(1H-indol-3-yl)-1-methyl-1-(1-phenylethylcarbamoyl)-ethyl!-carbamicacid 2-fluoro-5-methyl-benzyl ester;

carbamic acid, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-1-(4-pyridinyl)ethyl!amino!ethyl!-, 2-benzofuranylmethyl ester,monohydrochloride, R-(R*,S*)!;

carbamic acid, 1-(1H-indol-3-ylmethyl)-2-methyl(phenylmethyl)amino!-2-oxoethyl!-, 2-benzofuranylmethyl ester,(S)-;

carbamic acid, 1-(1H-indol-3-ylmethyl)-2-methyl(phenylmethyl)amino!-2-oxoethyl!-, benzo b!thien-2-ylmethyl ester,(S)-.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat respiratory disorders in a mammal suffering therefrom, and apharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating respiratorydisorders in a mammal such as a human comprising administering atherapeutically effective amount of a compound according to Formula I.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat inflammation in a mammal suffering therefrom, and apharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating inflammation ina mammal such as a human comprising administering a therapeuticallyeffective amount of a compound according to Formula I.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat gastrointestinal disorders in a mammal suffering therefrom, and apharmaceutically acceptable carrier.

Another aspect of the invention is a method for treatinggastrointestinal disorders in a mammal such as a human comprisingadministering a therapeutically effective amount of a compound accordingto Formula I.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat eye diseases such as dry eye and conjunctivitis in a mammalsuffering therefrom, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating eye diseases ina mammal such as a human comprising administering a therapeuticallyeffective amount of a compound according to Formula I.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat allergies in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.

Another aspect of the invention is a method for treating allergies in amammal such as a human comprising administering a therapeuticallyeffective amount of a compound according to Formula I.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat diseases of the central nervous system in a mammal sufferingtherefrom, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating diseases of thecentral nervous system in a mammal such as a human comprisingadministering a therapeutically effective amount of a compound accordingto Formula I.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective totreat migraine in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.

Another aspect of the invention is a method for treating migraine in amammal such as a human comprising administering a therapeuticallyeffective amount of a compound according to Formula I.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of compound according to Formula I effective totreat pain arising from neurogenic inflammation or inflammatory pain.

Another aspect of the invention is a method for treating pain such aspain arising from neurogenic inflammation in inflammatory pain status.

Another aspect of the invention is a pharmaceutical compositioncomprising an amount of a compound according to Formula I effective intreating conditions associated with aberrant neovascularization:rheumatoid arthritis, atherosclerosis, and tumor cell growth.

Another aspect of the invention is a method of treating conditionsassociated with aberrant neovascularization: rheumatoid arthritis,atherosclerosis, and tumor cell growth.

Another aspect of the invention is using the compounds as imaging agentsfor imaging NK₁ receptors in vivo.

Processes for preparing the compounds and novel intermediates areincluded in the invention.

DETAILED DESCRIPTION OF THE INVENTION

The following terms are descriptive of the compounds of the instantinvention.

The alkyl groups contemplated by the invention include straight,branched, or cyclic carbon chains of from 1 to 8 carbon atoms exceptwhere specifically stated otherwise. Representative groups are methylethyl, propyl, isopropyl, n-propyl, n-butyl, iso-butyl, sec-butyl,2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl,2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like.

The cycloalkyl groups contemplated by the invention comprise thosehaving 3 to 6 carbon atoms.

The alkoxy groups contemplated by the invention comprise both straightand branched carbon chains of from 1 to 6 carbon atoms unless otherwisestated. Representative groups are methoxyl, ethoxy, propoxy, i-propoxy,t-butoxy, and hexoxy.

The term halogen is intended to include fluorine, chlorine, bromine, andiodine.

The term aryl is intended to include substituted or unsubstitutedphenyl, naphthyl, biphenyl, and indanyl. The substituents include one ormore substituents such as halogens, nitro, alkyl, alkoxy, alkylthio,hydroxy, trifluoromethyl, and others as specified or as would occur toone skilled in the art.

The term arylalkyl is as described above for the two terms individually.

The term heterocyclic comprises substituted or unsubstituted pyridyl, 2-or 3-indolyl, thienyl, quinolyl, furanyl, isoquinolyl, benzofuranyl, andbenzothiophenyl.

The term amide/ester replacement refers to such moieties asketomethylene, methyleneoxy, tetrazole, 1,2,4-oxadiazole, and thiazole,etc. See for example Fincham, et al, J Med Chem, 1992;35:1472-1482 orSaunders, et al., J Med Chem, 1990;33:1128-1138.

The compounds of the instant invention are highly selective antagonistsof the tachykinin receptor.

One such compound (Ex. 15) is an antagonist of the NK₁ receptor incontrast to substance-P methyl ester which is a known selective NK₁receptor agonist. See Table I below.

                  TABLE I    ______________________________________    NK.sub.1 Antagonist Activity             pk.sub.B /pA.sub.2    Example    Guinea Pig Trachea.sup.a                            Guinea Pig Ileum.sup.b    ______________________________________    15         7.4          7.8    20         7.0          7.7    22         7.0          7.8    45         7.2          8.0    47         7.3          8.4    53         8.1          8.6    54         7.9          8.3    63         8.7          9.5    64         7.1          8.7    67         --           7.9    ______________________________________     .sup.a Ireland S J, et al., Regulatory Peptides 1988; 22:93.     .sup.b McKnight A T, et al., Br J Pharmacol 1991; 104: 355-60.

As can be seen from the data in Table I above, the compounds of theinvention (for example, Ex. 15), is a tachykinin NK₁ receptor antagonistin a number of in vitro NK₁ preparations, i.e., it antagonizes thepharmacological action of the selective NK₁ receptor agonist substance-Pmethylester on these tissues with a pK_(B) of about 8. Therefore, itcould be of use in therapeutic disorders where attenuation of the NK₁receptor response is an appropriate form of intervention.

These compounds are active in vivo as NK₁ receptor antagonists (seeTable II). They antagonize the ability of a NK₁ receptor selectiveagonist (SPOMe) to induce plasma protein extravasation in the guinea pigbladder. The protocol is similar to that described by Eglezos, et al.,Eur J Pharmacol 1991;209:277-279.

                  TABLE II    ______________________________________    Guinea Pig Plasma Extravasation    Example      ID.sub.50 (mg/kg IV)    ______________________________________    22           0.64    45           0.61    47           0.13    53           0.071    54           0.051    63           0.024    66           2.8    67           0.91    ______________________________________

The compounds of the invention were also evaluated in three tachykininbinding assays. For the NK₁ receptor measurement of the binding of ¹²⁵I-BH!. Substance-P, 0.1 nM to guinea pig cerebral cortex membranes wasmeasured as in Lee C M, et al, Eur J Pharmacol 1986;130:209 and in Br JPharmacol 1990;99:767.

For the NK₂ receptor measurement of the binding of ¹²⁵ I!-iodohistidylneurokinin A (0.1 nM) to hamster urinary bladder membrane was measuredas described in Buck, Shatzer Life Sci 1988;42:2701.

For the NK₃ receptor measurement of the binding of ³ H!-Senktide (2 nM)to a guinea pig cerebral cortex membrane was taken as described in Lee CM, above.

See Table III below for the binding data for representative compounds ofthe invention. This table shows in vitro NK₁ receptor binding data forcertain compounds of the invention.

                  TABLE III    ______________________________________    In Vitro NK.sub.1 Receptor Binding Data    Example      Binding IC.sub.50 (nM)    ______________________________________     1           341     3           218     4           198     6            75     7           306    15            36    16           702    20            64    21            27    22            17    23           168    24           185    27           306    29           487    35           233    36            70    37           290    38           100    39           10,000    40           210    41           >10,000    42           140    43           100    44           110    45            14    46           110    47            10    48           230    49           120    50           120    51           230    52            49    53            39    54            19    55           >1000    56           3200    57           3400    58           1700    60           >1000    63            9    ______________________________________

Table II shows the concentration of the compounds of the instantinvention which is needed to displace 50% of a specific radioligand (¹²⁵ I! Bolton Hunter labeled Substance-P) from tachykinin NK₁ receptorsites in guinea pig cerebral cortex membranes. It is a measure of theaffinity these compounds have for this receptor.

As can be seen from the binding data above, several of these compoundshave high affinity for the NK₁ receptor.

Compounds of the invention are expected to be useful in treatingdisorders mediated by tachykinins such as respiratory disorders,especially asthma.

They are also expected to be useful in treating inflammation such asarthritis, gastrointestinal disorders such as colitis, Crohn's disease,and irritable bowel syndrome.

They are further expected to be useful in treating and/or preventing eyediseases such as dry eye and conjunctivitis.

They are further expected to be useful in treating allergies such asrhinitis (common cold), and eczema.

The compounds are expected to treat vascular disorders such as anginaand migraine.

They are further expected to be useful in preventing and/or treatingdiseases of the central nervous system such as schizophrenia.

Scheme I below illustrates the synthesis of Examples 1-8 and 35,CBZ-Trp-OPFP (carbobenzoxy-Trp-pentafluorophenyl) was treated withN-methyl benzylamine in EtOAc to give Examples 1-3 when using theappropriate tryptophan stereochemistry (i.e., Example 2 uses R-Trp etc).Examples 4-8 were prepared using the same pentafluorophenyl ester oftryptophan as above but this time it was reacted with RS,R or Sα-methylbenzylamine using EtOAc as the solvent. The compound of Example35 was prepared by reacting the above PFP ester with 3,5 di- CF₃ benzylalcohol.

    __________________________________________________________________________    SCHEME I     ##STR13##     ##STR14##    Example Number                  •                    Example Number •                                     ▪    __________________________________________________________________________    1             RS                    4              RS                                     RS    2             R 5              R R    3             S 6              R S                    7              S S                    8              S R    __________________________________________________________________________     Reagents:     a) PhCH.sub.2 N(Me)H;     b) PhCH(Me)NH.sub.2 ;     c) (3,5diCF.sub.3)PhCH.sub.2 OH

In Scheme II (see below) the versatile intermediate, CBZ-tryptophanylpentafluorophenyl ester was treated with a variety of arylmethylamines.Example 9 was prepared using 4-chlorobenzylamine in ethyl acetate.Similarly, Example 10 was prepared using1,2,3,4-tetrahydronaphthyl-1-amine under similar conditions to that forExample 9. Another versatile intermediate shown in Scheme II is theN-terminal unprotected tryptophanyl benzylamide, treatment of this indry dichloromethane with 1-phenylethanol in the presence of4-nitrophenylchloroformate yielded Example 11. ##STR15##

Scheme III below outlines the synthesis of Examples 12-18, α-Methyltryptophan methylester was initially treated with benzylchloroformate inaqueous 1,4-dioxane and in the presence of base to give theCBZ-protected ester. This ester was then saponified with lithiumhydroxide to the corresponding acid which was then treated withdicyclohexylcarbodiimide (DCC) in the presence of pentafluorophenol(PFP-OH) to give CBZ-α-methyl tryptophan pentafluorophenyl ester. Thisactive ester was treated with benzylamine to give Example 12. The sameester was also treated with N-methylbenzylamine to yield Example 13.Examples 14-18, 36, 37, 38, 39, and 40 were prepared again from thisPFP-ester using the appropriate amine.

    __________________________________________________________________________    SCHEME III     ##STR16##     ##STR17##    Example Number                 •      ▪                                  R.sup.1    __________________________________________________________________________    12           RS           --  --    13           R            --  --    14           R            RS  4ClPh    15           R            S   Ph    16           S            S   Ph    17           S            R   Ph    18           R            R   Ph    36           R            R or S                                  4-CH.sub.3 Ph    37           R            R or S                                  4-CH.sub.3 Ph    38           R            S   c-Hexyl    39           R            R,S (3,5-diCF.sub.3)Ph    40           R            R,S 4-OCH.sub.3 Ph    __________________________________________________________________________     Reagents:     a) i. PhCH.sub.2 OCOCl; ii. LiOH; iii. DCC,PfP;     b) PhCH.sub.2 NH.sub.2 ;     c) PhCH.sub.2 N(Me)H;     d) R.sup.1 CH(Me)NH.sub.2 -

The synthetic routes described in Scheme IV below involve the veryuseful intermediate α-methyltryptophanyl-1-phenethylamide which can besynthesized from Example 15 by hydrogenation of the CBZ-N-terminalprotecting group using Pearlmans catalyst in ethanol. This free aminemay then be reacted with the appropriate chloroformate or activecarbonate to give Examples 20-22, 41-54, and 63-65. Example 19 wasprepared by the action of the amine on benzyl isocyanate.

    __________________________________________________________________________    SCHEME IV     ##STR18##     ##STR19##    Example Number                 •      ▪                                R.sup.1    __________________________________________________________________________    19           R            S --    20           R            S 4MeOPhCH.sub.2    21           R            S 4ClPhCH.sub.2    22           R            S 4CH.sub.3PhCH.sub.2    41           S            S 4-pyridylCH.sub.2    42           S            S 3-thienylCH.sub.2    43           R            S 2-thienylCH.sub.2    44           R            S                                 ##STR20##    45           R            S 2-Naphthalene CH.sub.2    46           R            S                                 ##STR21##    47           R            S 2-FPhCH.sub.2    48           R            S 3-FuranylCH.sub.2    49           R            S 2-FuranylCH.sub.2    50           R            S 3-FPhCH.sub.2    51           R            S 4-FPhCH.sub.2    52           R            S 2,3 diFPhCH.sub.2    53           R            S 2,4 diFPhCH.sub.2    54           R            S 2,5 diFPhCH.sub.2    63           R            S 2-BenzofuranylCH.sub.2    64           R            S 2-BenzothiophenylCH.sub.2    65           R            S (2-F,5-CH.sub.3)PhCH.sub.2    __________________________________________________________________________

As illustrated in Scheme V below, abrine (N-methyl tryptophan) gavebenzyloxycarbonyl-abrine when exposed to benzylchloroformate in aqueous1,4-dioxane in the presence of base. This N-protected abrine was thenused to prepare many derivatives having various C-terminal groups.Example 25 was synthesized by preparing an active ester of the abrinederivative with pentafluorophenol and dicyclohexylcarbodiimide thenreacting this with N-methylbenzylamine. Similarly, Examples 23, 26, and28 were prepared by the reaction of this active ester with various arylamines such as 4-trifluoromethylbenzylamine (Example 26) and4-chlorobenzylamine (Example 28). Examples 24 and 27 were made byreaction of the same active ester with α-methylbenzylamine(1-phenethylamine).

    __________________________________________________________________________    SCHEME V     ##STR22##     ##STR23##    Example Number                  •        ▪                                   Ar    __________________________________________________________________________    23            S              --                                   Ph    24            S              S --    25            S              --                                   --    26            S              --                                   C.sub.6 H.sub.4 -4CF.sub.3    27            S              R --    28            S              --                                   C.sub.6 H.sub.4 -4Cl    __________________________________________________________________________     Reagents:     a) PhCH.sub.2 OCOCl;     b) i. DCC,PfP; ii. ArCH.sub.2 NH.sub.2 ;     c) i. DCC,PfP; ii. PhCH.sub.2 (Me)NH.sub.2 ;     d) i. DCC,PfP; ii. PhCH.sub.2 N(Me)H

Methods for derivatizing the N-terminus of the abrine-containingcompounds were carried out via the methods shown in Scheme VI below.Abrine was treated with 9-fluorenylmethylchloroformate in aqueous1,4-dioxane with sodium carbonate to give the FMOC-protected abrine. Theactive ester of this (PFP-OH,DCC) was then treated with benzylamine inethyl acetate to give the amide which was deprotected under the standardconditions of 20% piperidine in DMF. This free amine was then treatedwith 4-chlorobenzyl chloroformate, 4-trifluoromethylbenzylchloroformate,and 2,3 dimethoxybenzyl-4'-nitrophenyl carbonate to give Examples 29,30, and 31, respectively. ##STR24##

Examples 32, 33, 34, and 55-59 were prepared according to Scheme VIIbelow. The appropriate amino acids were reacted to give theirCBZ-protected derivatives. These compounds were then treated via theiractive esters with the appropriate amine or alcohol to produce thedesired product.

    __________________________________________________________________________    SCHEME VII     ##STR25##     ##STR26##    Example Number •                      ▪                                Ar     R.sup.1    __________________________________________________________________________    32             R,S                      --        (4-Cl)Ph                                       H    33             R,S                      --        (4-Br)Ph                                       H    34             R,S                      --        (3,4-diOH)Ph                                       H    55             R,S                      S         3-Indazole                                       CH.sub.3    56             R,S                      S         3-((5-F)Indole)                                       CH.sub.3    57             R,S                      R,S       3(N-Me Indole)                                       CH.sub.3    58             R  S         2-Naphthalene                                       CH.sub.3    59             R,S                      S         --     --    __________________________________________________________________________     Reagents:     a) PhCH.sub.2 OCOX; X is a leaving group     b) i. activation of carboxylic acid; ii. PhCH(R.sup.1)NH.sub.2 -     c) DCC, PhCH(CH.sub.3)OH

Example 60 was prepared by the method shown in Scheme VIII below. Themethyl ester of 3-benzothiophenylalanine was reacted withdibenzyldicarbonate to give the CBZ-protected derivative. This was thentreated with base to give the carboxylic acid, which subsequently wasactivated and reacted with the appropriate amine. ##STR27##

Example 61 was prepared by the method shown in Scheme IX below. CBZ α-Metryptophan was activated to give the pentafluorophenyl ester (describedin Scheme III) and reacted with the appropriate amino alcohol. This wasthen cyclized with Lawesson's reagent to give product. ##STR28##

Example 62 was prepared by the method shown in Scheme X below. Themethyl ester of tryptophan was converted to the N-formyl derivativewhich was subsequently treated with (BOC)₂ O to protect the indolenitrogen. The isonitrile was then formed and alkylated withbromoacetonitrile. The resulting product was treated with hydrochloricacid followed by benzylchloroformate to give the urethane. Next, theBOC-group was removed and the ester hydrolysed with lithium hydroxide.The acid was then activated an subsequently condensed witha-methylbenzylamine. ##STR29##

Example 66 was prepared by the method shown in Scheme XI below. Themixed carbonate was obtained by reduction of the carboxylic acid andreaction with p-nitrophenylchloroformate. This was then treated with themethyl ester of α-methyl tryptophan to yield the urethane; which washydrolysed with base to give the acid. The resulting product was thenactivated as its p-nitrophenylester.

4-Acetyl pyridine was converted to the oxime, which was subsequentlyreduced to give the primary amine. This was reacted with thep-nitrophenyl-ester to give the amide. This was then converted to thehydrochloride salt. ##STR30##

Examples 67 and 68 were prepared by the method shown in Scheme XIIbelow.

The BOC-protected-(S)-tryptophan-N-hydroxy-succinimidyl ester wasreacted with N-methyl benzylamide to give theBOC-(s)-tryptophan-N-methyl-benzylamine which was deprotected with TFAto give the unprotected (S)-tryptophanyl-N-methyl benzylamide. This freeamine was then reacted with the benzothiophenyl carbonate to giveExample 68 and with the benzofuranylcarbonate to give Example 67.##STR31##

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository preparations, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

The powders and tablets preferably contain 5% to about 70% of the activecomponent. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth,methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax,cocoa butter, and the like.

The compounds of the invention include solvates, hydrates,pharmaceutically acceptable salts, and polymorphs (different crystallinelattice descriptors) of the compounds of Formula I.

The compounds of the present invention can have multiple chiral centersin the above Formula I depending on their structures. In particular, thecompounds of the present invention may exist as diastereomers, mixturesof diastereomers, or as the mixed or the individual optical enantiomers.The present invention contemplates all such forms of the compounds. Themixtures of diastereomers are typically obtained as a result of thereactions described more fully below. Individual diastereomers may beseparated from mixtures of the diastereomers by conventional techniquessuch as column chromatography or repetitive recrystallizations.Individual enantiomers may be separated by conventional methods wellknown in the art such as conversion to a salt with an optically activecompound, followed by separation by chromatography or recrystallizationand reconversion to the nonsalt form.

Where it is appropriate to form a salt, the pharmaceutically acceptablesalts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate,bromide, calcium acetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate (embonate), pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, theoclate, triethiodide, benzathine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum,calcium, lithium, magnesium, potassium, sodium, and zinc.

Cyclodextrin is one suitable inclusion in a pharmaceutical preparation.

The term "preparation" is intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid preparations can also beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

Preferably the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

EXAMPLE 1 ##STR32##

N-Methylbenzylamine (0.17 mL, 0.00126 mol) was added to a solution ofCBZ-RS-Tryptophan pentafluorophenyl ester (0.64 g, 0.00126 mol) in EtOAc(5 mL) and the residue stirred at room temperature for 2 hours. Thesolvent was removed in vacuo and the residue dissolved in EtOAc (50 mL)and washed with 2M hydrochloric acid (2×20 mL), water (2×10 mL), brine(20 mL), dried (MgSO₄) and the solvent evaporated in vacuo. The residuewas purified via column chromatography eluting withdichloromethane:methanol (9:1) to give the product as a white solid(0.31 g, 55%) mp 51°-55° C.;

IR (film): 3301 (NH, urethane), 1708 (C=0, urethane), 1636 (C=0, amide),1496, 1342, and 1232 cm⁻¹ ;

NMR (CDCl₃): 2.51 and 2.74 (3H, s, CH₃ N); 3.20 (2H, d, J=7 Hz,Trp--CH₂); 4.0-4.4 (2H, 2×m, ArCH₂ N amide ROT); 4.9-5.1 (3H, m, ArCH₂O, αCH); 5.83 and 5.89 (1H, d, J=8 Hz, NH carbamate amide ROT); 6.7-7.7(15H, m, aromatics); 8.2 and 8.3 (1H, s, NH, indole);

MS m/e (CI) 442 (M⁺ +1).

EXAMPLE 2 ##STR33##

Method as described for Example 3, Scheme I, but using CBZ-R-Tryptophanpentafluorophenyl ester. Yield (0.08 g, 35%); mp 50°-53° C.;

α!_(D) ²³ -27.2 (C=0.25, MeOH);

IR (film): 3296-2928, 1712 (urethane co), 1636 (amide I) and 1525 cm⁻¹(amide II);

NMR (DMSO-d₆): δ2.75 (3H, s.CH₃); 3.01 (1H, d.d, J=7.5 and 13.9 Hz, oneof Trp βCH₂); 444 (2H, s, CH₂ Ph); 4.54 (1H, m, αCH), 5.01 (2H, s, PhCH₂O); 6.97-7.37 (15H, m, aromatics); 7.57 (1H, d, J=7.7 Hz, urethane NH);10.7 (1H, S, indole NH);

MS m/e (CI) 442 M⁺ !.

EXAMPLE 3 ##STR34##

CBZ-L-tryptophan pentafluorophenyl ester (0.50 g, 1 nmol) was preparedin situ and reacted with benzylmethylamine (0.13 mL, 1 nmmol) inethylacetate (5 mL). The reaction mixture was stirred overnight at roomtemperature then washed with diluent HCl (1×10 mL), water (4×10 mL), anddried over MgSO₄. Removal of the solvent in vacuo resulted in a clearoil which was chromatographed to give the product (0.175 g, 40%); mp48°-50° C.;

α!_(D) ²³ =+30.4 (c=0.25, MeOH);

IR (film): 3305-2927, 1710 (urethane CO), 1635 (amide I) and 1530 cm⁻¹(amide II);

NMR (DMSO-d₆, 1340K): δ2.50 (3H, 3, CH₃); 3.01 (1H, d.d, J=7.3 and 13.8Hz, one of βCH₂); 4.43 (2H, s, NCH₂ Ph); 4.72 (1H, m, TrpαCH); 5.00 (2H,S, OCH₂ Ph); 7.02-7.35 (15H, m, aromatics); 7.57 (1H, b, urethane NH);10.65 (1H, s, indole NH);

MS m/e (CI) 442 M⁺ !.

EXAMPLE 4 ##STR35##

(RS) α-Methylbenzylamine (0.128 mL, 0.001 mol) was added to a solutionof (CBZ-RS-tryptophan pentafluorophenyl ester (0.533 g, 0.001 mol) inEtOAc (15 mL) and the mixture stirred at room temperature for 15 min.The solvent was removed in vacuo and the residue dissolved in EtOAc (50mL) and washed with 2M hydrochloric acid (2×20 mL), water (2×10 mL),brine (20 mL), dried (MgSO₄) and the solvent evaporated in vacuo. Theresidue was purified via column chromatography eluting with hexane:ethylacetate (8:2) to give Example 4 Scheme I as a white solid (0.33 g, 76%)mp 59°-62° C.;

NMR:(CD₃ SOCD₃): δ1.23 and 1.34 (3H, d, J=7 Hz, CHCH₃); 2.8-3.2 (2H, m,IndCH₂); 4.3 (1H, m, CH); 4.9 (3H, m, ArCH₂ O and NHCH); 6.9-7.4 (15H,aromatics and NH carbamate); 7.63 (1H, d, J=8 Hz, 4H-indole); 8.33 and8.41 (1H, d, J=8 Hz NH amide); 10.8 (1H, s, indole NH);

MS m/e (CI) 442 (M⁺ +H).

EXAMPLE 5 ##STR36##

CBZ-DL Tryptophan pentafluorophenyl ester (0.25 g, 0.5 mmol) wasprepared in situ, dissolved in ethylacetate (2.5 mL) and(R)-(+)-α-methylbenzylamine (0.06 mL, 0.5 mmol) was added. The reactionmixture was stirred at room temperature until no starting materialremained. The white precipitate was collected by filtration andrecrystallized from ethylacetate to give Example 5 Scheme I (0.10 g,44%); mp 169°-170° C.;

α!_(D) ²³ =+12.80 (c=0.5, MeOH);

IR (film): 3306, 1705 (urethane co), 1657 (amide I), and 1531 cm⁻¹(amide II);

NMR (DMSO-d₆): δ1.35 (3H, d, J=6.7 Hz, CH₃); 2.87 (1H, d.d, J=9.2 and14.3 Hz, one of Trp βCH₂); 3.06 (1H, d.d, J=4.8 and 14.3 Hz, one of TrpβCH₂); 4.36 (1H, m, CH(CH₃ Ph), 4.90-4.96 (3H, m, CH₂ Ph, αCH);6.94-7.35 (15H, m, aromatics); 7.63 (1H, d, J=7.8 Hz, urethane NH); 8.41(1H, d, J=7.8 Hz, amide NH); 10.8 (1H, s, indole NH);

MS m/e (CI) 442 M⁺ !.

EXAMPLE 6 ##STR37##

Method as described for Example 5, Scheme 1, but using(S)-(-)-α-methylbenzylamine. Yield (0.09 g, 21%); mp 160°-161° C.;

α!_(D) ²³ =-26.0 (c=0.5, MeOH);

IR (film): 3330, 1709 (urethane co), 1658 (amide I) and 1514 cm⁻¹ (amideII);

NMR (DMSO-d₆): δ1.23 (3H, d, J=6.8 Hz, CH₃); 2.95 (1H, d.d, J=9.4 and14.3 Hz, one of Trp βCH₂); 3.08 (1H, d.d, J=5.4 and 14.3 Hz, one of TrpβCH₂); 4.32 (1H, m, CH(CH₃)Ph), 4.86-4.94 (3H, m, PhCH₂, αCH); 6.95-7.34(15H, m.aromatics); 7.63 (1H, α, J=7.7 Hz, urethane NH); 8.33 (1H, d,J=7.5 Hz, amide NH); 10.8 (1H, s, indole NH);

MS m/e (CI) 442 M⁺ !.

EXAMPLE 7 ##STR38##

Example 5, Scheme I, but using (S)-(-)-α-methylbenzylamine method asdescribed for Example 5, Scheme I. Recrystallization from ethyl acetategave (0.057 g, 13%); mp 168°-170° C.;

α!_(D) ²³ =-11.6 (c=0.5, MeOH);

IR (film): 3294, 1704 (urethane CO), 1656 (amide I) and 1536 cm⁻¹ (amideII);

NMR (DMSO-d₆): δ1.35 (3H, d, J=6.9 Hz, CH₃); 2.86 (1H, d.d, J=9.2 and14.3 Hz, one of βCH₂); 3.06 (1H, d.d, 5=4.8 and 14.3 Hz, one of βCH₂);4.36 (1H, m, CH(CH₃)Ph); 4.90-4.96 (3H, m, PhCH₂, Trp αCH); 6.94-7.35(15H, m, aromatics); 7.63 (1H, d, J=7.9 Hz, urethane NH); 8.41 (1H, d,J=7.7 Hz, amide NH); 10.8 (1H, s, indole NH);

MS m/e (CI) 442 M⁺ !.

EXAMPLE 8 ##STR39##

CBZ-S-Trp pentafluorophenyl ester (0.50 g, 1 mmol) was prepared in situ,then dissolved in ethyl acetate and (R)-(+)-α-methylbenzylamine (0.13mL, 1 mmol) was added. The reaction mixture was stirred at roomtemperature until no starting material remained. The white precipitatewas collected by filtration and purified by chromatography to give theproduct (0.077 g, 17%); mp 160°-163° C.;

α!_(D) ²³ =+24.4 (c=0.5, MeOH);

IR (film): 3307, 1704 (urethane CO), 1657 (amide I) and 1517 cm⁻¹ (amideII);

NMR (DMSO-d₆): δ1.24 (3H, d, J=7.0 Hz, CH₃); 2.95 (1H, d.d, J=9.4 and14.3 Hz, one of βCH₂); 3.08 (1H, d.d, J=5.4 and 14.3 Hz, one of βCH₂);4.32 (1H, m, CH(CH₃)Ph); 4.86-4.94 (3H, m, PhCH₂, Trp αCH); 6.95-7.34(15H, m, aromatics); 7.63 (1H, d, J=7.7 Hz, urethane NH); 8.32 (1H, d,J=7.8 Hz, amide NH); 10.8 (1H, s, indole NH);

MS m/e (CI) 442 M⁺.

EXAMPLE 9 ##STR40##

Method as described for Example 3, Scheme I, but using4-chlorobenzylamine. Yield (0.05 g, 11%); mp 177°-179° C.;

α!_(D) ²³ =+10.8 (C=0.5, MeOH);

IR (film): 3291, 1704 (urethane CO), 1658 (amide II), and 1535 cm⁻¹(amide I);

NMR (DMSO-d₆): δ2.95 (1H, d.d, J=9.1 and 14.5 Hz, one of Trp βCH₂); 3.13(1H, d.d, J=5.3 and 14.5 Hz, one of Trp βCH₂); 4.20-4.36 (3H, m, αCH,NHCH₂); 4.97 (2H, s, PhCH₂ O); 6.94-7.46 (14H, m, aromatics); 7.62 (1H,d, J=7.8 Hz, urethane NH); 8.52 (1H, bt, amide NH); 10.8 (1H, s, indoleNH);

MS m/e (CI) 462 M⁺.

EXAMPLE 10 ##STR41##

Method as described for Example 3, Scheme I; but using1,2,3,4-tetrahydro-1-napthylamine. Yield (0.298 g, 64%); mp 73°-76° C.;

IR (film): 3298-2863, 1707 (urethane CO), 1651 (amide I) and 1538 cm⁻¹(amide II);

NMR (DMSO-d₆): δ1.52-1.87 (4H, m, CH₂ CH₂); 2.70 (2H, m, CH₂ CH₂ Ph) ;2.91-3.16 (2H, m, Trp βCH₂); 4.32 (1H, m, αCH); 4.96 (3H, m, PhCH₂,NHCHPh); 6.74-7.37 (14H, m, aromatics); 7.63 (1H, m, urethane NH); 8.21(1/2H, d, J=9.4 Hz, amide NH); 8.32 (1/2H, d, J=8.8 Hz, amide NH);10.81, 10.79 (1H, 2×s, indole NH);

MS m/e (CI) 468 M⁺ !.

EXAMPLE 11 ##STR42##

A solution of (RS) sec-phenethyl alcohol (2 g, 0.0163 mol) and drypyridine (1.3 mL, 0.0163 mol) in dry dichloromethane (10 mL) was cooledto 0° C. A solution of 4-nitrophenyl chloroformate (3.28 g, 0.0163 mol)in dry dichloromethane (25 mL) was added dropwise over 15 minutes andthe resulting solution stirred at room temperature for 15 hours. Thesolvent was removed in vacuo (the temperature being kept below 30° C.)and ether (50 mL) was added and the precipitate was removed byfiltration. The solvent was removed in vacuo below 30° C. to give thecrude mixed carbonate, νmax 1765 cm⁻¹ (c=0), which was used withoutfurther purification.

R,S-Tryptophan benzylamide (0.5 g, 0.0018 mol) and triethylamine (0.18mL, 0.0018 mol) were dissolved in dry DMF (5 mL). A solution of themixed carbonate (0.52 g, 0.0025 mol) in DMF (5 mL) was added dropwiseover 5 minutes, there was an immediate yellow coloration upon additionof the mixed carbonate, and the yellow solution was stirred at roomtemperature for 5 hours. The reaction mixture was poured into water (50mL) and extracted with EtOAc (3×10 mL). The organic phase was washedwith dilute aqueous NaOH (approx. 1M) until the disappearance of theyellow color (approx. 5×20 mL) and then with saturated aqueous citricacid (5×20 mL), water (10 mL), brine (20 mL), dried (MgSO₄), and thesolvent removed in vacuo. The crude product was purified by columnchromatography, eluting with dichloromethane:ethanol (9:1) to give theurethane, Example 11, Scheme II, as a white solid (0.61 g, 77%); mp128°-132° C.;

IR (film): 3317 (NH), 1706 (C=0), carbamate), 1659 (C=0, amide), 1497,1456, 1378, and 1355 cm⁻¹ ;

NMR (DMSO-d₆): 1.35 and 1.4 (3H, d, J=7 Hz, CHCH₃); 2.8-3.2 (2H, m,IndCH₂), 4.3 (3H, m, CONHCH₂ Ph, CH); 5.1 (1H, m, PhCHO); 6.9-7.3 (15H,aromatics and carbamate NH); 7.6 (1H, m, 4H-indole); 8.45 (1H, m, amideNH); 10.7 (1H, m, indole NH);

MS m/e (CI): 442 (M⁺ +H).

EXAMPLE 12 ##STR43##

Benzyl chloroformate (0.85 mL, 0.005 mol) was added in one portion to avigorously stirred suspension of R,S-α-Me-Trp methyl ester (1 g, 0.0043mol) and potassium carbonate (2 g, 0.015 mol) in dioxane (15 mL) andwater (1 mL). The mixture was stirred at room temperature for 2 hours,after which time t.l.c. analysis indicated the consumption of startingmaterial. The solvent was removed in vacua. The residue was treated with2M hydrochloric acid (10 mL), water (40 mL), and extracted with EtOAc(3×20 mL). The organic phase was washed with water (2×20 mL), brine (10mL), dried (MgSO₄), and the solvent removed in vacuo to give theN-protected amino ester as an off-white solid (1.39 g, 87%) which wasused in the next reaction without further purification. νmax (film):3345 br (NH), 1718 br (C=0, ester and carbamate) cm⁻¹. δ(CDCl₃): 1.63(3H, s, α--CH₃); 3.60 (5H, br.m, OCH₃ and CH₂ -Ind); 5.08 (2H, m, ArCH₂O); 5.5 (1H, br.s, NH urethane); 6.8-7.5 (11H, aromatics); 8.3 (1H,br.s, NH indole).

A mixture of this ester (1.49 g, 0.004 mol) and lithium hydroxidemonohydrate (0.84 g, 0.02 mol) in THF (15 mL) and water (5 mL) wasstirred vigorously at room temperature for 15 hours. The solution wasextracted with EtOAc (3×10 mL) and the organic phase discarded. Theaqueous phase was acidified with 2M hydrochloric acid (approx. 20 mL)and extracted with EtOAc (3×20 mL). The organic phase was washed withwater (20 mL), brine (20 mL), dried (MgSO₄), and the solvent removed invacuo to give the acid (Scheme III) as a light brown oil (1.31 g, 88%)which was used in the next step without further purification. νmax(film): 3389 (OH), 1770 (C=0, acid), and 1708 (C=0, carbamate) cm⁻¹.

This crude carboxylic acid (1.1 g, 0.003 mol),N,N'-dicyclohexylcarbodiimide (DCC) (0.618 g, 0.003 mol) andpentafluorophenol (PFP) (0.6 g, 0.0033 mol) were dissolved in EtOAc (20mL) and the reaction mixture stirred at room temperature for 1 hour. Themixture was filtered to remove the white solid and benzylamine (0.35 mL,0.0033 mol) was added and the mixture stirred for 10 hours at roomtemperature. The solvent was removed in vacuo and the crude product waspurified by column chromatography, eluting with dichloromethane:methanol(8:2), giving the benzamide, Example 12, Scheme III, as a white solid(0.97 g, 73%); mp 117°-119° C.;

IR (film): 3337 (NH), 1709 (C=0, carbamate), 1657 (C=0, amide), 1517,1456, and 1352 cm⁻¹ ;

NMR (DMSO-d₆): 1.37 (3H, s, α-Me); 3.33 (2H, m, Ind-CH₂); 4.28 (2H, d,J=5 Hz, NCH₂ Ph); 5.04 (2H, m, Ph-CH₂ O); 6.9-7.5 (16H, aromatics andcarbamate); 8.2 (1H, br.s, amide NH); 10.83 (1H, s, indole NH);

MS m/e (CI); 442 (M⁺ +H).

EXAMPLE 13 ##STR44## Step 1

A solution of R-α-methyl tryptophan methylester (37.16 g, 160.0 mmol) indry THF (800 mL) and triethylamine (19.43 g, 192 mmol) was cooled to 0°C. and treated with benzylchloroformate (30.03, 176 mmol) in dry THF(200 mL) dropwise. This was allowed to warm to room temperature slowly,then the solvent removed in vacuo. The residue was redissolved in EtOAc(500 mL), washed with H₂ O (500 mL), 2N HCl (500 mL), saturated NaHCO₃solution (500 mL), then H₂ O (500 mL). The organic phase was dried overMgSO₄, filtered, and evaporated to dryness in vacuo. The residue waspurified by silica gel chromatography using 60% Et₂ O in n-hexane aseluant to give the product.

α!_(D) ²⁰ =+31.7° (c=1, MeOH).

Step 2

The CBZ-αMe-R-tryptophan methyl ester (69.15 g, 150 mmol) was dissolvedin THF (800 mL), cooled to 0° C., and treated with LiOH (30 g in 250 mLH₂ O). MeOH was added (150 mL) and the mixture stirred for 3 hours. Thesolvent was removed in vacuo. The residue was diluted with H₂ O (500 mL)and extracted with CH₂ Cl₂ (2×300 mL). The aqueous phase was acidifiedusing 2M citric acid and extracted with CH₂ Cl₂ (2×500 mL). The organicphase was washed with water, dried (MgSO₄), and filtered and evaporatedto dryness to give the crude acid, 57.5 g (2:1 mix acid:ester). Thiscrude material was used in Step 3.

Step 3

The crude carboxylic acid from Step 2 above was redissolved in EtOAc(320 mL) and treated with pentafluorophenol (21 g, 114 mmol), followedby the dropwise addition of a solution of N,N'-dicyclohexylcarbodiimide(23.5 g, 114 mmol) in EtOAc (150 mL). This was stirred 18 hours at roomtemperature. The reaction mixture was then filtered, and the filtrateevaporated to dryness. The solid residue was redissolved in CH₂ Cl₂ (200mL) and absorbed onto silica, and purified by chromatography using 50%EtOAc in n-hexane to give the product 49.77 g (64%) fromα-methyl-R-tryptophan methylester;

IR (film): 1785, 1709, and 1520 cm⁻¹ ;

NMR (CDCl₃): δ1.72 (3H, s); 3.44 (1H, d, J=14.7 Hz); 3.66 (1H, d, J=14.7Hz); 5.15 (2H, m,); 5.22 (1H, br.s); 6.97 (1H, d, J=2 Hz); 7.09 (1H, t,J=7.5 Hz); 7.22 (1H, t, J=8.0 Hz, 7.34 (6H, m); 7.58 (1H, d, J=7.9 Hz);8.11 (1H, br.s). ##STR45##

A solution of CBZ-α-methyl-R-tryptophan pentafluorophenyl ester (250 mg,0.50 mmol) in EtOAc (50 mL) was treated with N-benzylmethylamine (900mg, 7.40 nmol) and stirred at room temperature for 18 hours. Thismixture was washed with 2N HCl (50 mL), then H₂ O (50 mL). The organicphase was dried (MgSO₄), filtered, and evaporated to give a cruderesidue which was purified by reverse-phase chromatography using 50%MeOH in H₂ O as eluant to give the product as a white foam (40 mg, 18%);mp 64°-68° C. (MeOH/H₂ O);

IR (nujol mull): 1703 and 1620 cm⁻¹ ;

NMR (DMSO-d₆): δ1.30 (3H, s); 2.90 (3H, brs); 3.20 (1H, d, J=14 Hz);3.50 (1H, d, J=14 Hz); 4.60 (2H, br); 5.00 (2H, br); 6.8-7.6 (16H, m);10.9 (1H, br.s); MS (CI) m/e 456 (11, M⁺ +H), 335 (30), 304 (48) 263(4.5), 91 (100);

Analysis calculated for C, H, N; C₂₃ H₂₉ N₃ O₃.0.25CCl₄ : C, 68.68; H,5.92; N, 8.51. Found: C, 68.68; H, 5.90; N, 8.38.

EXAMPLE 14 ##STR46##

A solution of CBZ-α-methyl-R-tryptophan pentafluorophenyl ester (1000mg, 1.929 mmol) in EtOAc (50 mL) was treated at room temperature with 4chloro-α-methylbenzylamine (1100 mg, 7.069 mmol) for 1 hour withstirring. The reaction mixture was then washed with 2N HCl (80 mL), thenH₂ O (100 mL). The organic phase was dried over MgSO₄, filtered, andevaporated to dryness in vacuo. The residue was purified bychromatography using 20% Et₂ O in CH₂ Cl₂ as eluant to give the productas a white foam and a 1:1 mixture of diasteroisomers (820 mg, 87%); mp56°-58° C. (Et₂ O/CH₂ Cl₂);

IR (nujol mull): 710 and 1651 cm⁻¹ ;

NMR (DMSO-d₆): δ1.20-1.40 (6H, m); 3.10-3.50 (2H, m); 4.80 (1H, m); 5.00(2H, s); 6.80-7.50 (14H, m); 7.90 1H, d, J=8 Hz); 8.1 (1H, d, J=8 Hz);10.80 (1H, s).

EXAMPLE 15 ##STR47##

A solution of CBZ-α-methyl-R-tryptophan pentafluorophenyl ester (730 mg,1.40 nmol) in EtOAc (15 mL) was treated with S(-)α-methylbenzylamine(940 mg, 7.76 mmol) and left stirring at room temperature for 1 hour.The mixture was washed with 2M HCl (20 mL) then H₂ O (20 mL). Theorganic phase was dried over MgSO₄, filtered, and evaporated to drynessin vacuo. The residue was then subject to reverse phase chromatographyusing 80% MeOH; 20% H₂ O as eluant to give the product as a white foam(150 mg, 24%); mp 107°-109° C. (H₂ O/MeOH);

α!_(D) ²⁰ =+13° (c=0.5, MeOH);

IR (film): 3460-3400, 1711, 1658, 1495, and 1251 cm⁻¹ ;

NMR (DMSO-d₆): δ1.32 (3H, d, J=7 Hz); 1.38 (3H, s); 3.20-3.40 (2H, m);4.90 (1H, m); 5.00 (2H, s); 6.80 (1H, s); 6.90 (1H, t, J=7 Hz); 7.00(1H, t, J=7 Hz); 7.01-7.40 (12H, m); 7.50 (1H, d, J=8 Hz); 8.00 (1H, d,J=8 Hz); 10.80 (1H, s); MS (CI) 456 (30, M⁺ +H), 130 (100), 91 (57), 105(33).

Analysis calculated for C, H, N, C₂₈ H₂₉ N₃ O₃.0.5H₂ O: C, 72.39; H,6.51; N, 9.04%. Found: C, 72.53; H, 6.48; N, 8.98%.

EXAMPLE 16 ##STR48##

Method as for Example 15, Scheme III except usingCBZ-α-methyl-S-tryptophan pentafluorophenyl ester (142 mg, 23%); mp107°-110° C. (MeOH:H₂ O);

IR (film): 3327, 1716, and 1653 cm⁻¹ ;

NMR (DMSO-d₆): δ1.20-1.40 (6H, m); 3.10-3.40 (2H, m); 4.90 (1H, m); 5.00(2H, s); 6.80-7.50 (16H, m); 7.90 (1H, d, J=8 Hz); 10.80 (1H, br.s).

Analysis calculated for C, H, N, C₂₈ H₂₉ N₃ O₃.0.25H₂ O: C, 73.10; H,6.46; N, 9.13%. Found: C, 73.40; H. 6.41; N, 9.18%.

EXAMPLE 17 ##STR49##

Method as for Example 15, Scheme III except usingCBZ-α-methyl-S-tryptophan pentafluorophenyl ester andR(+)-α-methylbenzylamine (190 mg, 30%); mp 109°-111° C. (MeOH/H₂ O);

α!_(D) ²⁴ =-13.2° (c=0.5, MeOH);

IR (film): 1719 and 1654 cm⁻¹ ;

NMR (DMSO-d₆): 1.34 (3H, d, J=7.9 Hz); 1.39 (3H, s); 3.28-3.36 (2H, m);4.92 (1H, m); 5.04 (2H, s); 6.82 (1H, s); 6.87 (1H, br); 6.93 (1H, t,J=7.6 Hz); 7.02 (1H, t, J=7.0 Hz); 7.22-7.47 (11H, m); 7.50 (1H, d,J=7.8 Hz); 8.02 (1H, d, J=8.2 Hz); 10.8 (1H, s); MS (CI) m/e 456 (25, M⁺+H), 130 (100), 91 (73), 105 (35), 304 (29);

Analysis calculated for C, H, N, C₂₈ H₂₉ N₃ O₃.0.25H₂ O: C, 73.10; H,6.46; N, 9.13%. Found: C, 73.27; H, 6.45; N, 9.22%.

EXAMPLE 18 ##STR50##

Method as for Example 15, Scheme III, except using(R)(+)α-methylbenzylamine (150 mg, 24%); mp 63°-68° C. (MeOH/H₂ O);

α!_(D) ²⁸ =+9.4° (c=0.5, MeOH);

IR (film): 17H, 1658 cm⁻¹ ;

NMR (DMSO-d₆): δ1.28 (3H, d, J=6.8 Hz); 1.34 (3H, s); 3.16-3.30 (2H, m);4.89 (1H, m); 5.04 (2H, s); 6.89 (1H, s); 7.00 (1H, t, J=7.9 Hz);7.20-7.45 (13H, m); 7.48 (1H, d, J=7.8 Hz); 7.88 (1H, d, J=7.5 Hz);16.80 (1H, s);

MS (CI) m/e 456 (20, M⁺ +H), 130 (100, 191, 150).

EXAMPLE 19 ##STR51##

A solution of Example 15, Scheme III (17 g, 37 mmol) in EtOH (200 mL)was treated with 20% Pd(OH)₂ (1 g, 6% w/w) and put under an atmosphereof hydrogen at 30° C. at a pressure of 45 psi for 3 hours. The reactionmixture was then filtered and evaporated to dryness in vacuo, theresidue was purified by SiO₂ chromatography using 0.5% NH₄ OH, 5% MeOH,94.5% CH₂ Cl₂ as eluant to give the product (8.1 g, 62%); mp 124.5°-125°C.;

α!_(D) ²⁰ =+7.0° (c=1, MeOH);

IR (film): 1643, 1512, and 1454 cm⁻¹ ;

NMR (CDCl₃): δ1.42 (3H, d, J=6.9 Hz); 1.46 (3H, s); 1.53 (2H, br.s);2.81 (1H, d, J=14.2 Hz); 3.46 (1H, d, J=14.2 Hz); 5.02 (1H, dq, J=7 Hz);6.71 (1H, d, J=2.2 Hz); 7.17 (7H, m); 7.33 (1H, d, J=8.0 Hz); 7.59 (1H,d, J=7.8 Hz); 7.82 (1H, d, J=8 Hz); 8.02 (1H, s);

MS (CI) m/e 322 (100, M⁺ +H);

Analysis calculated for C, H, N, C₂₀ H₂₃ N₃ O: C, 74.74; H, 7.21; N,13.07%. Found: C, 74.7; H, 7.25; N, 13.04%. ##STR52##

To a stirred solution of the amine (Scheme IV) (321 mg, 1.0 mmol) in THF(10 mL) was added a solution of benzyl isocyanate (146 mg, 1.1 mmol) inTHF (5 mL) dropwise. After 1 hour, the solvent was removed in vacuo andthe residue chromatographed using 4% MeOH/CH₂ Cl₂. Crystallization fromether gave product (404 mg, 89%); mp 184°-187° C.;

α!_(D) ²⁰ =27° (c=1, MeOH);

IR (film): 3500-3200 (NH), 1646 (broad, CO, urea and amide), 1557, 1455,1265, 741, and 700 cm⁻¹ ;

NMR (CDCl₃): δ1.28 (3H, d, J=6.9 Hz, CHC₃); 1.48 (3H, s, CCH₃); 3.11(1H, d, J=14.6 Hz, one of CH₂ indole); 3.41 (1H, d, J=14.6 Hz, one ofCH₂ indole); 4.14 (1H, d, J=15.1 and 5.8 Hz, one of CH₂ Ph); 4.24 (1H,dd, H=15.1 and 5.9 Hz, one of CH₂ Ph); 4.82-4.92 (1H, m, CHCH₃); 5.12(1H, s, CH₂ NHCONH); 5.20-5.30 (1H, m, CH₂ NHCONH); 6.74 (1H, d, J=2.2Hz, indole, C₂ H); 7.00-7.30 (14H, m, aromatics and CONHCH); 7.51 (1H,d, J=7.7 Hz, indole C₄ -H); 8.22 (1H, s, indole NH);

MS m/e (CI⁺) 455 (52) (M⁺ +H) , 348 (11) , 334 (27), 322 (100), 304(49), 173 (47), 131 (25), 130 (61), 105 (40), 91 (85);

Analysis calculated for C, H, N.

EXAMPLE 20 ##STR53## 1) To a stirred solution of 4nitrophenylchloroformate (2.01 g, 10 mmol) in acetone (30 mL), cooled inan ice bath, was added 4-methoxybenzylalcohol (1.38 g, 10 mmol) followedby the dropwise addition of a solution of triethylamine (1.01 g, 10mmol) in acetone (10 mL). Left to stir overnight, filtered offtriethylaminehydrochloride, solvent removed under vacuum. Residue takenup in ethyl acetate (50 mL), washed with citric acid solution (2×30 mL),sodium carbonate solution (5×30 mL), brine (2×30 mL), dried over MgSO₄,and solvent removed in vacuo. Crystallization from ether gave carbonate(2.7 g, 89%); mp 99°-100° C.;

IR (film): 1747 (CO, carbonate), 1617, 1519, 1353, 1279, 1255, 1034, 866cm⁻¹ ;

NMR (CDCl₃): δ3.83 (3H, s, CH₃ O); 5.24 (2H, s, CH₂ O); 6.90-6.95 (2H,m, ##STR54## 7.35-7.40 (4H, m, ##STR55## 8.23-8.30 (2H, m, ##STR56## MSm/e (CI⁺): 303 (10) (M⁺ +H), 277 (2), 260 (5), 241 (3), 149 (9), 140(61), 122 (44), 121 (100);

Analysis calculated for C, H, N.

2) A solution of carbonate (364 mg, 1.2 mmol), the amine (321 mg, 1.0mmol), and 4-dimethylamino-pyridine (122 mg, 1.0 mmol) in DMF (20 mL)was stirred overnight before solvent was removed under vacuum. Residuetaken up in ethyl acetate (50 mL) and washed with citric acid solution(2×50 mL), brine (30 mL), 2N NaOH solution (5×50 mL), brine (30 mL),dried over MgSO₄, filtered, and solvent removed under vacuum. Residuechromatographed using 2% MeOH/CHCl₂ and crystallization from ether gaveproduct (360 mg, 80%); mp 86°-94° C.;

α!_(D) ¹⁷ =+16.7° (c=1, MeOH);

IR (film): 3500-3200 (NH), 1713 (CO, urethane), 1652 (CO, amide), 1614,1515, 1457, 1246, 1176, 1070, 822, 742, and 701 cm⁻¹ ;

NMR (CDCl₃): δ1.31 (3H, d, J=6.9 Hz, CHCH₃); 1.60 (3H, s, CCH₃); 3.24and 3.46 (each 1H each d, J=14.7 Hz, each one of CH₂ indole); 3.79 (3H,s, OMe); 4.95-5.05 (3H, m, CH₂ OCONH and CONHCH); 5.27 (1H, s, OCONH);6.35-6.45 (1H, br.d, CONHCH); 6.75 (1H, s, indole C₂ -H); 6.85 (2H, d,J=8.6 Hz, ortho protons to OMe group); 7.09 (1H, t, J=7.4 Hz, indole C₅or C₆ -H); 7.15-7.30 (8H, m, CH₂ Ph, indole C₅ or C₆ H, meta protons toOMe group); 7.33 (1H, d, J=8.0 Hz, indole C₇ -H); 7.57 (1H, d, J=7.8 Hz,indole C₄ -H); 7.95 (1H, s, indole NH);

Analysis calculated for C, H, N.

EXAMPLE 21 ##STR57## 1) Method as for Example 20, Scheme IV, except used4-chlorobenzyl alcohol (1.42 g, 10 mmol) to give a crystalline carbonate(2.9 g, 94%) from ether;

mp 135°-138° C.;

IR (film): 1761 (CO, carbonate), 1524, 1492, 1350, 1261, 1215 cm⁻¹ ;

NMR (CDCl₃): δ5.26 (2H, s, CH₂ O); 7.35-7.40 (6H, m, aromatics);8.25-8.30 (2H, m, ##STR58## MS m/e (CI⁺): 308 (6) (M⁺ +H) , 292 (4), 278(7) , 266 (15), 264 (41), 140 (43), 127 (82), 125 (100);

Analysis calculated for C, H, N, Cl.

2) Method as for Example 20, Scheme IV, except used 4-chlorobenzylcarbonate (368 mg, 1.2 mmol). Chromatography using 3% MeOH/CH₂ Cl₂followed by crystallization from ether gave a crystalline product (434mg, 89%); mp 98°-100° C.;

α!_(D) ²⁰ =+12.5° (c=1, MeOH);

IR (film): 3450-3200 (NH), 1712 (CO, urethane), 1651 (CO, amide), 1494,1457, 1251, 1073, 742, and 700 cm⁻¹ ;

NMR (CDCl₃): δ1.29 (3H, d, J=6.9 Hz, CHCH₃); 1.63 (3H, s, CCH₃); 3.26(1H, d, J=14.8 Hz, one of CH₂ indole); 3.45 (1H, d, J=14.8 Hz, one ofCH₂ indole); 4.95-5.05 (3H, m, CH₂ O and CHCH₃); 5.43 (1H, s, OCONH);6.27 (1H, d, J=7.5 Hz); 680 (1H, s, indole, C₂ -H); 7.05-7.30 (11H, m,CHPh, Cl-Ar, indole C₅ and C₆ -H); 7.34 (1H, d, J=8.0 Hz, indole C₇ -H);7.58 (1H, d, J=7.9 Hz, indole C₄ -H); 8.01 (1H, s, indole NH);

Analysis calculated for C, H, N.

EXAMPLE 22 ##STR59## 1) Method as for Example 20, Scheme IV except usedα-methylbenzylalcohol (1.22 g, 10 mmol) to give a crystalline carbonate(2.3 g, 80%) for ethyl acetate;

mp 93°-95° C.;

IR (film): 1750 (CO, carbonate), 1536, 1349, 1268, 1218, 865 cm⁻¹ ;

NMR (CDCl₃): δ2.37 (3H, s, CH₃); 5.26 (2H, s, CH₂ O); 7.15-7.40 (6H, m,aromatics); 8.24-8.30 (2H, m, ##STR60## MS m/e (CI⁺): 288 (6) (M⁺ +H);244 (41), 239 (12), 198 (49), 140 (36), 122 (25), 106 (51), 105 (100);

Analysis calculated for C, H, N.

2) Method as for Example 20, Scheme IV, except used4-methylbenzylcarbonate (345 mg, 1.2 mmol). Residue chromatographedusing 2% MeOH/CH₂ Cl₂ and crystallization from ether gave product (350mg, 75%); mp 85°-95° C. (Needles);

α!_(D) ²⁴ +15.5° (c=1, MeOH);

IR (film): 3500-3200 (NH, 3059, 3028, 2977, 2930, 1709 (CO, urethane),1652 (CO, amide), 1494, 1457, 1251, 1071, 742, and 700 cm⁻¹ ;

NMR (CDCl₃): δ1.30 (3H, d, J=6.9 Hz, CHCH₃); 1.61 (3H, s, CCH₃); 2.34(3H, s, Me-aryl); 3.24 (1H, d, J=14.7 Hz, one of CH₂ indole); 3.46 (1H,d, J=14.8 Hz, one of CH₂ indole); 4.95-5.07 (3H, m, CH₂ O and CHCH₃);5.31 (1H, s, OCONH); 6.38 (1H, d, J=7.7 Hz, CONHCH); 6.77 (1H, d, J=2.2Hz, indole C₂ -H); 7.05-7.30 (11H, m, CHPh, pMe-Ph, indole C₅ and C₆-H); 7.33 (1H, d, J=8.1 Hz, indole C₇ -H); 7.58 (1H, d, J=7.7 Hz, indoleC₄ -H); 7.98 (1H, s, indole NH);

Analysis calculated for C, H, N.

EXAMPLE 23 ##STR61##

Benzylchloroformate (0.85 mL, 0.005 mol) was added in one portion to avigorously stirred suspension of S-abrine (1 g, 0.0040 mol), potassiumcarbonate (1.2 g, 0.009 mol) in dioxane (15 mL) and water (1 mL). Themixture was stirred at room temperature for 1 hour, after which timet.l.c. analysis indicated the consumption of starting material. Thesolvent was removed in vacuo. The residue was treated with 2Mhydrochloric acid (20 mL), water (40 mL), and extracted with EtOAc (3×30mL). The organic phase was washed with water (10 mL), brine (2×10 mL),dried (MgSO₄), and the solvent removed in vacuo to give the N-protectedamino acid (Scheme V) as a dark straw-colored oil (1.25 g, 77%) whichwas used in the next reaction without further purification; νmax (film):3345 br (OH), 1740 shoulder (C=0 acid) and 1684 cm⁻¹ v. broad (C=0,carbamate).

The carboxylic acid (0.85 g, 0.0024 mol), N,N'-dicyclohexylcarbodiimide(DCC) (0.56 g, 0.0024 mol) and pentafluorophenol (PFP) (0.44 g, 0.0027mol) were dissolved in EtOAc (20 mL) and the reaction mixture stirred atroom temperature for 1 hour. The mixture was filtered to remove thewhite solid. Benzylamine (0.3 mL, 0.0026 mol) was added and the mixturestirred for 10 hours at room temperature. The solvent was removed invacuo and the crude product was purified by column chromatography,eluting with dichloromethane:methanol (9:1) giving Example 23 as a whitesolid (0.66 g, 63%); mp 48°-54° C.;

IR (film): 3326 (NH), 1695 (shoulder, C=0, carbamate), 1662 (C=0,amide), 1547, 1497, and 1402 cm⁻¹ ;

NMR (DMSO-d₆): 2.88 (3H, br.s, NHCH₃); 3.10 (1H, br, m, CH_(a) H_(b)Ind); 3.33 (1H, m, CH_(a) H_(b) Ind); 4.32 (2H, d, J=6 Hz, NHCH₂ Ph);4.8-5.2 (3H, m, ArCH₂ O and CH); 6.8-7.7 (15H, m, aromatics andcarbamate NH); 8.65 (1H, s, br, amide NH); 10.85 (1H, s, indole NH); MSm/e (CI) 442 (M⁺ +H).

EXAMPLE 24 ##STR62##

A solution of CBZ-S-abrine pentafluorophenyl ester (100 mg, 0.20 mmol)in EtOAc (10 mL) was treated with S-(-)-α-methylbenzylamine (470 mg,4.00 mmol) at room temperature for 10 minutes with stirring. The mixturewas then washed with diluent HCl (20 mL) then H₂ O (20 mL). The organicphase was dried over MgSO₄, filtered, and evaporated to dryness invacuo. The residue was purified by chromatography using 10% Et₂ O:90%CH₂ Cl₂ as eluant to give the product as a white foam (68 mg, 77%); mp58°-60° C. (Et₂ O/CH₂ Cl₂);

IR (nujol mull): 1681 and 1656 cm⁻¹ ;

NMR (DMSO-d₆): δ1.40 (3H, d, J=7 Hz), 2.80 (3H, s); 3.00 (1H, m); 3.20(1H, m); 4.80-5.10 (4H, m); 6.80-7.70 (15H, m); 8.50 (1H, d, J=9 Hz);10.80 (1H, br);

MS (CI) m/e, 456 (55, M⁺ +H), 290 (100), 91 (55).

Analysis calculated for C, H, N, C₂₈ H₂₉ N₃ O₃.0.25H₂ O: C, 73.10; H,6.46; N, 9.13%. Found: C, 73.34; H, 6.41; N, 9.19%.

EXAMPLE 25 ##STR63##

A solution of CBZ-S-abrine pentafluorophenyl ester (100 mg, 0.20 mmol)in EtOAc (20 mL) was treated with N-methyl benzylamine (470 mg, 3.90mmol) for 10 minutes at room temperature. The mixture was washed with 2NHCl (20 mL, then H₂ O (20 mL). The organic phase was dried (MgSO₄),filtered, evaporated, and the residue subject to reverse phasechromatography using 60%-70% MeOH in H₂ O to give the product as a whitefoam (66 mg, 75%); mp 44°-45° C. (MeOH/H₂ O);

α!_(D) ²⁰ =-49° (c 0.1, MeOH);

IR (nujol mull): 1683 and 1633 cm⁻¹ ;

NMR (DMSO-d₆, 360° K.): δ2.80 (3H, s); 2.90 (3H, s); 3.0-3.4 (2H, m);4.50 (2H, m); 5.00-5.60 (3H, br, m); 6.90-7.60 (15H, m); 10.60 (1H, br);

MS (CI) m/e 456 (42, M⁺ +H), 335, 2.90 (100), 91 (62).

EXAMPLE 26 ##STR64##

A solution of CBZ-S-abrine pentafluorophenyl ester (100 mg, 0.20 mmol)in EtOAc (20 mL) was treated with 4-trifluoromethylbenzylamine (1.23 g,7.03 mmol) for 10 minutes at room temperature. The organic phase waswashed with diluent HCl (25 mL) then H₂ O (25 mL), dried (MgSO₄),filtered, and evaporated to dryness in vacuo. The residue was purifiedby silica gel chromatography using CH₂ Cl₂ then 20% Et₂ O in CH₂ Cl₂ aseluant to yield the product as a white foam (84 mg, 85%); mp 55°-57° C.(Et₂ O/CH₂ Cl₂);

α!_(D) ²⁰ =-58° (c=0.1, MeOH);

IR (nujol mull): 1689 and 1660 cm⁻¹ ;

NMR (DMSO-d₆): δ2.80 (3H, s); 3.10 (1H, m); 3.30 (1H, m); 4.40 (2H, d,J=6 Hz); 4.80-5.10 (3H, br.m); 6.90-7.70 (14H, m); 8.70 (1H, br); 10.90(1H, br);

MS (CI) m/e 510 (50, M⁺ +H), 344 (72), 130 (62), 91 (100).

Analysis calculated for C, H, N, C₂₈ H₂₆ N₃ O₃ F₃ : C, 66.00; H, 5.14;N, 8.25%. Found: C, 66.17; H, 5.15; N, 8.24%.

EXAMPLE 27 ##STR65##

A solution of CBZ-S-abrine pentafluorophenyl ester (100 mg, 0.20 mmol)in EtOAc (10 mL) was treated with R-(+)-α-methylbenzylamine (470 mg,4.00 mmol) at room temperature for 10 minutes with stirring. The mixturewas then washed with 2N HCl (20 mL) then H₂ O (20 mL). The organic phasewas dried over MgSO₄, filtered, and evaporated in vacuo to give aresidue that was purified by chromatography using 10% Et₂ O in CH₂ Cl₂as eluant to give the product as a white foam (62 mg, 71%);

mp 51°-56° C. (Et₂ O/CH₂ Cl₂);

α!_(D) ²⁰ =-40° (c=0.1, MeOH);

IR (nujol mull): 1690 and 1653 cm⁻¹ ;

NMR (DMSO-d₆): δ1.30 (3H, d, J=7 Hz); 2.80 (3H, br.s); 3.00-3.30 (2H,m); 4.81-5.10 (4H, br.m); 6.90-7.70 (15H, m); 8.40 (1H, br.d, J=9 Hz);10.80 (1H, br.s);

MS (CI) m/e 456 (33, M⁺ +H); 412 (30), 335 (55), 290 (100), 91 (58).

Analysis calculated for C, H, N, C₂₈ H₂₉ N₃ O₃.0.25H₂ O: C, 73.10; H,6.46; N, 9.13%. Found: C, 73.26; H, 6.32; N, 9.11%.

EXAMPLE 28 ##STR66##

A solution of CBZ-S-abrine pentafluorophenyl ester (100 mg, 0.20 mmol)in EtOAc (30 mL) was treated at room temperature with4-chlorobenzylamine (600 mg, 4.20 mmol) at room temperature for 10minutes. The reaction mixture was then washed with 2N HCl (50 mL) thenH₂ O (50 mL). The organic phase was dried over MgSO₄, filtered, andevaporated to dryness in vacuo. The residue was purified bychromatography using 10% Et₂ O:CH₂ Cl₂ as eluant to give the product asa white foam (62 mg, 60%); mp 56°-58° C. (Et₂ O/CH₂ Cl₂);

α!_(D) ²⁰ =-65° (c=0.25, MeOH);

IR (nujol mull): 1683 and 1659 cm⁻¹ ;

NMR (DMSO-d₆, 340° C.): δ2.80 (3H, s); 3.00-3.40 (2H, m); 4.30 (2H, d,J=6 Hz); 5.00 (3H, br); 6.90-7.60 (14H, m); 8.40 (1H, br); 10.60 (1H,br);

MS (CI) m/e 476 (55, M⁺ +H), 432 (45), 335 (51), 310 (75), 130 (65), 91(100).

Analysis calculated for C, H, N, C₂₇ H₂₆ N₃ O₃ Cl: C, 68.13; H, 5.51; N,8.83%. Found: C, 68.02; H, 5.40; N, 8.76%.

EXAMPLE 29 ##STR67## Step 1

To a stirred solution of S-abrine (4.00 g, 18.3 mmol) and sodiumcarbonate (4.27 g, 40.3 mmol) in aqueous dioxan (1:2, 60 mL), cooled inan ice bath, was added 9-fluorenylmethyl chloroformate (5.69 g, 22 mmol)dropwise in dioxan (40 mL). Mixture was stirred for 4 hours withcooling, then overnight at room temperature. Dioxin was removed in vacuobefore diluting with water (100 mL) to obtain a clear solution.Extracted with ether (3×100 mL), ether discarded, aqueous layeracidified using 2N HCl and extracted with ethyl acetate (3×200 mL).Organic layers combined, washed with brine (2×100 mL), dried over MgSO₄,filtered, and solvent removed in vacuo to obtain product (8 g, 99%) as awhite non-crystalline solid; mp 80°-85° C.;

α!_(D) ²⁰ =-67.7° (c=1, MeOH);

IR (film): 3500-2400, 1715 (CO, carboxylic acid), 1685 (CO, urethane),1479, 1452, 1404, 1323, 1266, 1198, 1153, 759, and 740 cm⁻¹ ;

NMR (DMSO-d₆) (340K): δ2.77 (3H, s, NCH₃); 3.05-3.20 (1H, m, one of CH₂indole); 3.30 (1H, d.d, J=15.2 and 5.0 Hz, one of CH₂ indole); 4.00-4.30(3H, br.m, CHCH₂ OCONH); 4.89 (1H, d.d, J=10.2 and 5.0 Hz, CH₂ CHCO₂ H);6.90-7.10 (3H, m, aromatics); 7.20-7.55 (8H, m, aromatics); 7.83 (2H, d,J=7.5 Hz, fluorenyl, CH₃); 10.65 (1H, s, indole NH);

MS m/e (CI⁺): 441 (2) (M⁺ +H), 245 (2), 219 (14), 207 (9), 188 (5), 179(100), 130 (17). ##STR68##

To a stirred solution of Fmoc-S-abrine (4.40 g, 10 mmol) in ethylacetate (100 mL), cooled in an ice bath, was added pentafluorophenol(1.84 g, 10 mmol) followed by solid N,N'-dicyclohexylcarbodiimide (2.06g, 10 mmol). After 4 hours at 0° C., dicyclohexylurea was filtered offand the residue washed with cold ethyl acetate (10 mL). A solution ofbenzylamine (1.07 g, 10 mmol) was added to the filtrate dropwise over 10minutes (reaction complete after 15 minutes by IR). Reaction mixture waswashed with citric acid solution (2×20 mL), sodium hydrogen carbonatesolution (2×20 mL), brine (1×20 mL), dried over MgSO₄, and solventremoved under vacuum. Residue was chromatographed using 30 then 40%ethyl acetate in hexane to give (4.98 g, 94%) as white noncrystallinesolid; mp 74°-79° C.;

α!_(D) ²⁰ =-47° (c=1, MeOH);

IR (film): 3317 (NH), 3061, 2950, 1669 (br., CO, amide and urethane),1526, 1453, 1402, 1318, 1248, 1152, 1102, 741, and 700 cm⁻¹ ;

NMR (DMSO-d₆) (340K): δ2.83 (3H, s, NCH₃); 3.06 (1H, d.d, J=15.0 and 9.7Hz, one of CH₂ indole); 3.33 (1H, d.d, J=15.0 and 5.8 Hz, one of CH₂indole); 4.00-4.40 (3H, brm, CHCH₂ OCO); 4.30 (2H, d, J=5.9 Hz, NHCH₂Ph); 4.97 (1H, d.d, J=9.6 and 5.9 Hz, CHCH₂ indole); 6.95 (1H, t, J=7.3Hz, indole CH); 7.00-7.08 (2H, m, indole CH₂); 7.15-7.40 (10H, m,aromatics); 7.44 (1H, d, J=7.3 Hz); 7.51 (1H, d, J=7.4 Hz); 7.61 (1H, d,J=7.8 Hz); 7.82 (2H, d, J=7.6 Hz, fluorenyl CH₂); 8.20-8.30 (1H, br.m,CONH); 10.65 (1H, s, indole NH); MS m/e (CI⁺): 530 (1) (M⁺ +H), 309 (8),308 (35), 276 (6), 207 (24), 180 (36), 179 (100), 178 (90). ##STR69##

A solution of Fmoc-S-abrine benzylamide (4.0 g, 7.55 mmol) in 20%piperidine in DMF (20 mL) was stirred at room temperature for 5 minutesbefore removing the solvent under vacuum. Solid residue was stirredvigorously in pet. ether (100 mL), decanted liquid off, and repeated 5times before leaving to stir overnight in pet. ether (200 mL). Filteredoff crystalline product (2.2 g, 95%); mp 140°-142° C.;

α!_(D) ²⁰ =+29.1° (c=1, MeOH);

IR (film): 3306 (NH), 1651 (CO, amide), 1523, 1455, 1340, 1103, 742, and698 cm⁻¹ ;

NMR (DMSO-d₆) (340K): δ1.75 (1H, s, NH); 2.20 (3H, s, NCH₃); 2.85 (1H,d, J=14.2 and 7.2 Hz, one of CH₂ indole); 3.02 (1H, d.d, J=14.2 and 6.3Hz, one of CH₂ indole); 3.24 (1H, t, J=6.8 Hz, CHCH₂ indole); 4.19 (1H,d.d, J=15.1 and 5.6 Hz, one of CH₂ Ph); 4.30 (1H, d.d, J=15.0 and 5.9Hz, one of CH₂ Ph); 6.96 (1H, t, J=7.2 Hz, indole C₅ or C₆ H); 7.00-7.30(7H, m, CH₂ Ph and 2 indole CH₃); 7.34 (1H, d, J=8.0 Hz, indole C₇ -H);7.54 (1H, d, J=7.8 Hz, indole C₄ -H); 8.25 (1H, t, J=6.0 Hz, CONH);10.80 (1H, s, indole NH); MS m/e (CI⁺): 308 (100 (M⁺ +H), 277 (21), 276(12), 178 (34), 177 (64), 173 (80), 132 (22), 131 (46), 130 (30), 91(25). ##STR70## Step 4

To a stirred solution of 4-chlorobenzylalcohol (214 mg, 1.5 mmol) inethyl acetate (10 mL) at 0° C. was added solid triphosgene (148 mg, 0.5mol) followed by the dropwise addition of pyridine (119 mg, 1.5 mmol) inethyl acetate (5 mL) over 5 minutes. (After 30 minutes IR peak at 1776cm⁻¹.) Filtered off pyridine hydrochloride, removed solvent undervacuum, residue taken up in THF (5 mL) and added dropwise to a solutionof S-abrine benzylamide (307 mg, 1 mmol) and pyridine (119 mg, 1.5 mmol)in THF (20 mL). Intense yellow color as chloroformate added, followed bythe precipitation of pyridine hydrochloride. After 30 minutes removedsolvent under vacuum and residue chromatographed using 4% MeOH/CH₂ Cl₂to give product (270 mg, 56%) as noncrystalline solid; mp 52°-55° C.;

α!_(D) ²⁰ =-64.1 (c=1, MeOH);

IR (film): 3316 (NH), 1685 (CO, urethane), 1662 (amide), 1530, 1493,1455, 1399, 1318, 1142, 1092, 1014, and 742 cm⁻¹ ;

NMR (DMSO-d₆) (340K): δ2.85 (3H, s, NCH₃); 3.07 (1H, d.d, J=15.0 and 9.9Hz, one of CH₂ indole); 3.32 (1H, d.d, J=15.0 and 5.8 Hz, one of CH₂indole); 4.29 (2H, d, J=5.9 Hz, NHCH₂ Ph); 4.80-5.05 (3H, br.m, CH₂OCONHCH); 6.94 (1H, t, J=7.4 Hz, indole CH); 7.00-7.30 (11H, m,aromatics); 7.34 (1H, d, J=8.5 Hz, indole C₇ -H); 7.57 (1H, d, J=7.5 Hz,indole C₄ -H); 8.30-8.40 (1H, br.s, CONHCH₂); 10.65 (1H, s, indole NH);

MS m/e (CI⁺): 476 (32) (M⁺ +H), 434 (17), 432 (44), 369 (23), 297 (17),276 (100), 177 (24), 171 (24), 130 (57), 125 (51), 91 (24).

EXAMPLE 30 ##STR71## Step 5

Method as for Step 4, Example 29 using 4-trifluoromethylbenzyl alcohol(264 mg, 1.5 mmol) to give product (388 mg, 76%) as noncrystallinesolid;

mp 53°-57° C.;

α!_(D) ²⁰ =-63.1° (c=1, MeOH);

IR (film): 3307 (NH), 1663 (br, CO, amide and urethane), 1531, 1326,1124, 1067, 1018, 824, and 742 cm⁻¹ ;

NMR (DMSO-d₆) (340K): δ2.88 (3H, s, NCH₃) ; 3.10 (1H, d.d, J=14.9 and10.0 Hz, one of CH₂ indole); 3.33 (1H, d.d, J=14.9 and 5.7 Hz, one ofCH₂ indole); 4.30 (2H, d, J=5.8 Hz, NHCH₂ Ph); 4.90-5.10 (3H, m, CH₂ OCOand CHCH₂ indole); 6.93 (1H, t, J=7.3 Hz, indole CH); 7.00-7.35 (10H, m,aromatics); 7.50-7.65 (3H, m, indole C₇ -H and ##STR72## 8.30-8.40 (1H,br.s, CONH); 10.70 (1H, s, indole NH);

MS m/e (CI⁺): 510 (89) (M⁺ +H), 490 (12), 446 (15), 403 (41), 277 (34),276 (100), 171 (26), 159 (30), 130 (63), 91 (24).

EXAMPLE 31 ##STR73## Step 6

A mixture of 2,3-dimethoxybenzyl-4' nitrophenyl carbonate (400 mg, 1.2mmol) 4-dimethylaminopyridine (122 mg, 1.0 mmol), and S-abrinebenzylamide (307 mg, 1.0 mmol) was stirred in DMF (5 mL) for 3 hoursbefore solvent removed under vacuum. Residue taken up in ethyl acetate(50 mL) and washed with citric acid solution (2×50 mL), brine (30 mL),2N NaOH solution (5×50 mL), brine (30 mL), dried over MgSO₄, filtered,and solvent removed under vacuum. Residue chromatographed using 4%MeOH/CH₂ Cl to give product (500 mg, 100%) as white noncrystallinesolid;

mp 49°-54° C.;

α!_(D) ²⁰ =-45.3° (c=1, MeOH); IR (film): 3631, 3521, 3411, 3321, 2936,2836, 1665 (br, CO, urethane and amide), 1589, 1527, 1484, 1456, 1400,1186, 1151, 1085, 1009, 743, and 701 cm⁻¹ ; NMR (DMSO-d₆) (340K): δ2.84(3H, s, NCH₃); 3.07 (1H, d.d, J=14.9 and 9.7 Hz, one of CH₂ indole);3.32 (1H, d.d, J=14.9 and 5.9 Hz, one of CH₂ indole); 3.65 (3H, s,OCH₃); 3.79 (3H, s, OMe); 4.29 (2H, d, J=5.9 Hz, NHCH₂ Ph); 4.90-5.05(3H, m, CH₂ OCONCH); 6.65-6.75 (1H, br.s, one of CH₃ on OMe ring);6.90-7.10 (5H, m, aromatics); 7.15-7.30 (5H, m, aromatics); 7.33 (1H, d,J=8.1 Hz, indole C₇ -H); 7.57 (1H, d, J=7.8 Hz, indole C₉ -H); 8.25-8.35(1H, m, CONHCH₂); 10.65 (1H, s, indole NH);

MS m/e (CI⁺): 502 (13) (M⁺ +H), 459 (31), 458 (100), 277 (21), 276 (92),151 (87), 130 (35).

EXAMPLE 32 ##STR74##

Benzylchloroformate (0.94 g, 5.5 mmol) was added dropwise to asuspension of RS-4-chlorophenylalanine (1.0 g, 5.0 mmol) in 1M Na₂ CO₃(20 mL), cooled to 0° C. The reaction mixture was stirred for 5 hours atroom temperature, then acidified to pH 1 with concentrated HCl. Thewhite precipitate formed was collected by filtration and recrystallizedfrom ethyl acetate/hexane to give CBZ-RS-4-chlorophenylalanine (0.95 g,57%); mp 152°-155° C.;

IR (film): 3309, 1692 (urethane CO) and 1592 cm⁻¹ (amide II);

NMR (DMSO-d₆): δ2.83 (1H, d.d, J=10.9 and 13.7 Hz, one of βCH₂); 3.07(1H, d.d, J=4.3 and 13.7 Hz, one of βCH₂); 4.19 (1H, m, αCH); 4.97 (2H,s, CH₂ Ph); 7.31 (9H, m, aromatics); 7.65 (1H, d, J=8.5 Hz, NH); MS m/e(FAB) 334 MH!⁺. ##STR75##

CBZ-RS-4-chlorophenylalanine (0.5 g, 1.5 mmol) was dissolved in ethylacetate (5 mL) and dicyclohexyl-carbodiimide (0.31 g, 1.5 mmol) wasadded. Pentafluorophenol (0.28 g, 1.5 mmol) was added and the reactionwas stirred overnight at room temperature. The white precipitate formedwas removed by filtration and the filtrate concentrated in vacuo to givethe activated amino acid as a white solid which was redissolved in ethylacetate (10 mL). Benzylamine (0.16 mL, 1.5 mmol) was added and thereaction was stirred at room temperature for 1 hour. The whiteprecipitate was collected by filtration and purified by chromatography,followed by recrystallization from ethyl acetate to give the product(0.38 g, 60%);

mp 157°-158° C.;

IR (film): 3232, 1698 (urethane CO), 1657 (amide I), and 1553 cm⁻¹(amide II);

NMR (DMSO-d₆): δ2.82 (1H, d.d., J=10.3 and 13.4 Hz, one of βCH₂); 3.01(1H, d.d., J=4.5 and 13.4 Hz, one of βCH₂); 4.29 (3H, m, αCH, NHCH₂ Ph);4.97 (2H, s, PhCH₂ O); 7.17-7.36 (14H, m, aromatics); 7.58 (1H, d, J=8.6Hz, NH); 8.53 (1H, t, J=5.8 Hz, NHCH₂ Ph); MS m/e (CI) 423 M⁺.

EXAMPLE 33 ##STR76##

RS-4-Bromophenylalanine (0.98 g, 4 mmol) was suspended in a 1:1 mixtureof dioxan/water (20 mL). NaHCO₃ (0.67 g, 8 mmol) was added followed by asolution of dibenzyldicarbonate (1.37 g, 4.8 mmol) in dioxan (5 mL). Thereaction was stirred at room temperature overnight, then diluted withwater (20 mL). After washing with ether (2×20 mL), the aqueous layer wasacidified to pH 1 with concentrated HCl and then was extracted withethyl acetate (3×20 mL). The combined organic extracts were washed withwater (3×30 mL), dried over MgSO₄, and the solvent was removed in vacuo.The white solid obtained was crystallized from ethyl acetate/hexane togive the product (1.16 g, 77%); mp 161°-165° C.;

IR (film): 3310, 1694 (urethane CO), and 1532 cm⁻¹ (amide II);

NMR (DMSO-d₆): 2.81 (1H, d.d, J=10.7 and 13.7 Hz, one of βCH₂); 3.06(1H, d.d, J=4.3 and 13.7 Hz, one of βCH₂); 4.19 (1H, m, αCH); 4.97 (2H,s, CH₂ Ph); 7.31 (9H, m, aromatics); 7.76 (1H, d, J=8.5 Hz, NH); MS m/e(FAB) 378, 380 M⁺. ##STR77##

Method as for Example 32, Scheme VII. Yield (0.43 g, 61%); mp 163°-164°C.;

IR (film): 3296, 1698 (urethane CO), 1656 (amide I), and 1548 cm⁻¹(amide II);

NMR (DMSO-d₆) δ2.78 (1H, d.d, J=10.1 and 13.5 Hz, one of βCH₂); 2.98(1H, d.d, J=4.4 and 13.5 Hz, one of βCH₂); 4.27 (3H, m, αCH, NHCH₂ Ph);4.95 (2H, s, PhCH₂ O); 7.16-7.45 (14H, m, aromatics); 7.55 (1H, d, J=8.6Hz, NH); 8.51 (1H, t, J=5.6 Hz, NHCH₂ Ph); MS m/e (CI) 467, 469 M⁺.

EXAMPLE 34 ##STR78##

RS-3,4-Dihydroxyphenylalanine (0.99 g, 5 mmol) was suspended in a 1:1mixture of dioxan water. NaHCO₃ (0.84 g, 10 mmol) was added followed bya solution of dibenzyldicarbonate (1.72 g, 6 mmol) in dioxan (5 mL). Thereaction was stirred overnight at room temperature under an atmosphereof nitrogen. The solution was diluted with water (20 ml) and was washedwith ether (2×20 mL). The aqueous layer was then acidified to pH 1 withconcentrated HCl and was extracted with ethyl acetate (3×30 mL). Thecombined organic extracts were washed with water (3×30 mL) and then weredried over MgSO₄. The solvent was removed in vacuo and the brown oilobtained was partially purified by chromatography to give a brown oil(1.49 g, 90%). The oil (1.49 g, 4.5 mmol) was dissolved in ethyl acetate(15 mL), dicyclohexylcarbodiimide (0.93 g, 4.5 mmol), andpentafluorophenol (0.83 g, 4.5 mmol) were added and the reaction wasstirred overnight at room temperature. The precipitate formed wasremoved by filtration. Concentration of the filtrate in vacuo resultedin an orange oil (2.24 g) which was redissolved in ethyl acetate (10mL). Benzylamine (0.49 mL, 4.5 mmol) was added and the reaction wasstirred at room temperature under an atmosphere of nitrogen for 2 hours.Removal of the solvents in vacuo gave a brownish solid which waspurified by chromatography to give the product (0.29 g, 16%); mp207°-208° C.;

IR 3500-3000: 1703 (urethane CO), 1662 (amide I), 1609 (aromatic) and1547 cm⁻¹ (amide I);

NMR (DMSO-d₆): δ2.62 (1H, d.d, J=9.0 and 13.5 Hz, one of βCH₂); 2.81(1H, d.d, J=4.6 and 13.5 Hz, one of βCH₂); 4.18-4.33 (3H, m, αCH, NHCH₂Ph); 4.97 (2H, s, PhCH₂ O); 6.50 (1H, d, J=7.7 Hz, dihydroxy Phe H₅);6.60 (1H, d, J=7.7 Hz, dihydroxyPhe H₆); 6.67 (1H, s, dihydroxyPhe H₂);7.14-7.34 (10H, m, aromatics); 7.40 (1H, d, J=8.2 Hz, NH); 8.42 (1H,b.t, NHCH₂ Ph); 8.66 (2H, s, OH×2);

MS m/e (CI) 421 M⁺ !.

EXAMPLE 35 ##STR79##

Z-Trp-OPFP (0.2 g, 0.4 mmol) in EtOAc (30 mL) was treated with3,5-bis(trifluoromethyl)benzyl alcohol (0.12 g, 0.5 mmol) and DMAP (0.03g). This mixture was warmed to reflux for 20 minutes. The reactionmixture was washed with 2M HCl (2×50 mL), then H₂ O (2×50 mL), driedover MgSO₄, and evaporated to dryness in vacuo. The residue was purifiedby silica gel chromatography using 30% EtOAc in CH₂ Cl₂ as eluant, thenby reverse phase silica chromatography using 90% MeOH in H₂ O as eluantto give the product as a white solid (0.192 g, 85%); mp=134°-136° C.(MeOH/H₂ O);

α!_(D) ²⁰ =-8° (c=0.25, MeOH);

IR (film): 3409, 1745, 1715, 1506 cm⁻¹ ;

NMR (DMSO-d₆): δ3.15 (2H, m); 4.38 (1H, m); 4.98 (2H, s); 5.20 (1H, d,J=13.3 Hz); 5.32 (1H, d, J=13.4 Hz); 6.96 (1H, t, J=7.4 Hz); 7.05 (1H,t, J=8.1 Hz); 7.16 (1H, s); 7.30 (6H, m); 7.48 (1H, d, J=8.0 Hz); 7.90(1H, d, J=7.4 Hz); 7.99 (2H, s), 8.05 (1H, s); 10.82 (1H, br s);

MS m/e (CI): 565 (22%), 564 (21%), 521 (31%), 504 (36%), 131 (53%), 130(100%), 91 (83%);

Analysis calculated for C₂₈ H₂₂ N₂ O₄ F₆ : C, 59.58; H, 3.93; N, 4.96%,.Found: C, 59.87; H, 4.03; N, 4.98%.

EXAMPLES 36 AND 37

Phenylmethyl 1-(1H-indol-3-ylmethyl)-1-methyl-2-1-(4-methylphenyl)ethyl!amino!-2-oxoethyl!carbamate ##STR80##Phenylmethyl 1-(1H-indol-3-ylmethyl)-1-methyl-2-1-(4-methylphenyl)ethyl!amino!-2-oxoethyl!carbamate ##STR81## Step 1

4'-Methylacetophenone (93.9 g, 0.70 mol) was treated with EtOH (330 mL),H₂ O (400 mL), hydroxylamine hydrochloride (51.1 g, 0.735 mol),potassium hydroxide (94.7 g (85%), 1.44 mmol) and stirred for 12 hours.Solution poured into 1 L of water and treated with excess solidcarbondioxide. Filtration and recrystallization from ether/hexane gavepure product (92 g, 88%); mp 82°-84° C.; IR (film): 3327 (broad), 2925,1607, 1515, 1456, 1369, 1313, 1304, 1180, 1127, 1012, 927, 821, 749 cm⁻¹;

NMR (CDCl₃): δ, 2.29 and 2.37 each 3H, each s, CH₃ and Ar-CH₃)!; 7.19(2H, d, J=8.0 Hz, meta to Me); 7.52 (2H, d, J=8.1 Hz, ortho to Me); 9.27(1H, s, OH);

Analysis calculated for C₉ H₁₁ NO: C, 72.46; H. 7.43; N, 9.39%. Found:C, 72.35; H, 7.46; N, 9.38%.

Step 2

Oxime (29.83 g, 0.2 mol) dissolved in absolute EtOH (200 mL) and 10%palladium on carbon (2 g) added. Shaken for 3 hours under an atmosphereof hydrogen at 50 psi before filtering off catalyst using celite.Solvent removed under reduced pressure and residue taken up in 250 mL ofether and amine extracted into 15% hydrochloric acid (50 mL), aqueousphase basified using 50% NaOH solution and product extracted with ether(2×250 mL). Organic phase dried over K₂ CO₃, ether removed under reducedpressure, and residue distilled to give pure product (24.6 g, 91%); bp120° C. 10 mm Hg;

NMR (CDCl₃): δ1.37 (3H, d, J=6.6 Hz, CHCH₃); 1.47 (2H, s, NH₂); 2.33(3H, s, MeAr); 4.08 (1H, q, J=6.6 Hz, CHCH₃); 7.13 (2H, d, J=7.13 Hz);7.23 (2H, d, J=7.23 Hz); Analysis calculated for C₉ H₁₃ N.0.05H₂ O: C,79.42; H, 9.70; N, 10.29%. Found: C, 79.36; H, 9.76; N, 10.26%.

Step 3

To a stirred solution CBZ-(R)-α-methyltryptophan-pentafluorobenzyl ester(0.259 g, 0.5 mmol) in EtOAc (30 mL) was added amine (0.081 g, 0.6 mmol)and left to stir overnight at room temperature. Reaction mixture washedwith 10% citric acid solution (3×30 mL), H₂ O (30 mL), saturated NaHCO₃solution (2×30 mL)), brine (2×30 mL), dried over MgSO₄, and solventremoved under reduced pressure. Residue chromatographed using ether aseluant or normal phase silica. Crystallization from ether (2 mL) over 2days in freezer gave pure Isomer I (CAM 2676) (0.09 g, 38%). Thefiltrate was taken, solvent removed under reduced pressure, and a foamobtained from dichloromethane to give CAM 2677 (Mainly Isomer II,de >70% by NMR, 80 mg, 34%).

Isomer I

mp 155°-158° C.;

α!_(D) ²² =8.1° (c=0.5, MeOH);

IR (film): 3328 (br, NH), 2926, 1713 (CO, urethane), 1651 (CO, amide),1505, 1456, 1249, 1070, 81 cm⁻ ;

NMR (CDCl₃): δ1.28 (3H, Cl, CHCH₃, J=6.9 Hz); 1.61 (3H, s, CCH₃); 2.32(3H, s, CH₃ Ar); 3.26 (1H, d, J=14.8 Hz, one of CH₂ indole); 3.46 (1H,d, J=14.7 Hz, one of CH₂ indole); 4.97 (1H, p, J=7.2 Hz, NHCHCH₃); 5.07(2H, s, CH₂ Ph); 5.37 (1H, s, OCONH); 6.25-6.35 (1H, br.d, NHCH); 6.80(1H, s, indole C₂ H); 7.03-7.35 (12H, m, aromatics); 7.58 (1H, d, J=7.7Hz, indole C₄ -H); 7.95 (1H, s, indole NH);

MS m/e (CI⁺): 469 (M⁺, 0.2%), 362 (1%), 340 (1%), 318 (3%), 244 (3%),130 (16%), 119 (13%), 108 (20%), 91 (100%);

Analysis calculated for C₂₉ H₃₁ N₃ O₃.0.2H₂ O: C, 73.61; H, 6.69; N,8.88%. Found: C, 72.68; H, 6.63; N, 8.82%.

Isomer II

mp 62°-65° C.;

α!_(D) ²⁰ =+45° (c 0.5, MeOH);

IR (film): 3325 (br, NH₃), 3057, 2976, 2925 (CH str), 1715 (CO,urethane), 1652 (CO, amide), 1506, 1456, 1341, 1250, 1070, 817, 74 cm⁻¹;

NMR (CDCl₃): δ1.30 (3H, d, J=6.8 Hz, CH₃ CH); 1.56 (2.55H, s, CH₃ C formajor diastereoisomer); 1.60 (0.45H, s, CH₃ C for minordiastereoisomer); 2.31 (3H, s, Ar Me); 3.28 and 3.47 (each 1H, each d,J=14.7 Hz, each one of CH₂ indole); 4.92-5.06 (2H, m, CHCH₃, one of CH₂O), 5.11 (1H, d, J=12.1 Hz, one of CH₂ O); 5.27 (0.85H, s, OCONH); 5.40(0.15H, s, OCONH); 6.30-6.40 (1H, br.d, CHNH); 6.79 (1H, s, indole C₂H);7.05-7.35 (12H, m, aromatics); 7.57 (1H, d, J=7.9 Hz, indole C₄ H);8.06 (1H, s, indole NH);

MS m/e (CI⁺): 470 (M⁺ +H, 9%), 426 (2%), 352 (2%), 340 (11%), 318 (20%),244 (12%), 130 (94%), 119 (100%), 91 (88%)

Analysis calculated for C₂₉ H₃₁ N₃ O₃.0.2H₂ O: C, 73.61; H, 6.69; N,8.88%. Found: C, 70.56; H, 6.69; N, 8.88%.

EXAMPLE 38

Phenylmethyl R-(R*, R*)!-(2-(1-cyclohexylethyl)-amino!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl!carbamate##STR82##

A solution of Z-α-Me-R-Trp-OPFP ester (0.5 g, 0.1 mmol) in EtOAc (30 mL)was treated with cyclohexyl-1-ethyl amine (R isomer) (0.15 g, 1.2 mmol)and stirred for 2 hours at room temperature. The solvent was evaporatedand the residue purified by silica gel chromatography using 0-1% MeOH inCH₂ Cl₂ as eluant then by reverse phase silica gel chromatography using30% MeOH in H₂ O as eluant to give the product as an amorphous whitesolid (0.277 g, 62%); mp 51°-73° C.;

IR (film): 3318, 1709, 1650, 1516, 1655 cm⁻¹ ;

NMR (CDCl₃): δ0.73-0.98 (2H, m); 0.89 (3H, d, J=6.7 Hz); 1.00-1.30 (4H,m); 1.47-1.87 (5H, m); 1.56 (3H, s); 3.28 (1H, d, J=14.7 Hz); 3.48 (1H,d, J=14.5 Hz); 3.64-3.82 (1H, m); 5.08 (2H, br.s); 5.46 (1H, s); 6.13(1H, d, J=8.8 Hz); 6.87 (1H, d, J=2.2 Hz); 7.06 (1H, dt, J=1.0 and 7.0Hz); 7.14 (1H, dt, J=1.0 and 7.0 Hz); 7.30 (5H, m); 7.55 (1H, d, J=7.8Hz); 8.61 (1H, s);

Analysis calculated for C₂₈ H₃₄ N₃ O₃.0.25H₂ O: C, 72.31; H, 7.48; N,9.08%. Found: C, 72.24; H, 7.58; N, 8.81%.

EXAMPLE 39

Phenylmethyl (R,RS)- 2- 1-3,5-bis(trifluoromethyl)phenyl!ethyl!amino!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl!carbamate##STR83##

A solution of Z-αMe-R-Trp-OPFP ester (0.25 g, 0.50 mmol) in EtOAc (50mL) was treated with 3,5-bis-(trifluoromethyl)-α-methyl-benzylamine (RSmixture) (0.245 g, 0.950 mmol). The reacting mixture was stirred at roomtemperature for 1 hour, washed 2M HCl (2×50 mL) and H₂ O (2×50 mL). Theorganic phase was dried (MgSO₄), filtered, and evaporated to dryness invacuo. The residue was purified by silica gel chromatography using a10-80% gradient of EtOAc in hexane as eluant, then by reverse phasesilica gel chromatography using 80% MeOH in H₂ O as eluant to give theproduct as a white foam (0.232 g, 81%); mp 69°-73° C. (CH₂ Cl₂);

α!_(D) ²⁰ =+29 (c=0.25, MeOH);

IR (film): 3327, 1716, 1661, 1506, 1279 cm⁻¹ ;

NMR (DMSO-d₆) (340 K): δ1.25-1.45 (6H, m); 3.20 (1H) and 3.36 (1H) bothobscured by H₂ O; 5.04 (3H, m); 6.79 (1H, br.s); 6.87-7.10 (3H, m); 7.33(6H, m); 7.46 (1H, d, J=7.8 Hz); 7.87-8.15 (4H, m); 10.70 (1H, br.s);Analysis calculated for C₃₀ H₂₇ N₃ O₃ F₆ : C, 60.91; H, 4.60; N, 7.10%.Found: C, 60.93; H. 4.68; N, 6.96%.

EXAMPLE 40

Phenylmethyl (R,RS)- 1-(1H-indol-3-ylmethyl)-2-1-(4-methoxyphenyl)ethyl!amino!-1-methyl-2-oxoethyl!-carbamate ##STR84##

Z-R-α-Me-Trp-OPFP ester (0.2 g, 0.4 mmol) in EtOAc (30 mL) was treatedwith racemic 4-methoxy-α-methyl-benzylamine (0.15 g, 1.00 mmol) as themixture stirred at room temperature for 20 minutes. Triethylamine (1 g,9 mmol) was then added and the solution stirred a further 30 minutes.The reaction mixture was washed with 1M HCl (2×50 mL) then H₂ O (2×50mL), dried (MgSO₄), filtered, and evaporated to dryness in vacuo. Theresidue was separated by chromatography over silica gel using CH₂ Cl₂then 20% Et₂ O in CH₂ Cl₂ as eluant to give the product as a white foam(0.176 g, 94%);

mp 62°-65° C. (MeOH);

α!_(D) ²⁰ =+19° (c=0.5, MeOH);

IR (film): 3338, 2933, 1716, 1652, 1513, 1456, 1247 cm⁻¹ ;

NMR (DMSO-d₆): δ1.26 (1.5H, d, J=7.1 Hz); 1.30 (1.5H, d, J=7.1 Hz); 1.33(1.5H, s); 1.38 (1.5H, s); 3.30 (2H, obscured by H₂ O); 3.72 (1.5H, s);3.73 (1.5H, s); 4.85 (1H, m); 5.04 (2H, s); 6.79-6.95 (5H, m); 7.02 (1H,t, J=7.1 Hz); 7.20 (2H, dd, J=8.7 and 12.6 Hz); 7.34 (6H, m); 7.47 (1H,t, J=7.2 Hz); 7.81 (0.5H, d, J=8.0 Hz); 7.93 (0.5H, d, J=8.0 Hz); 10.80(1H, br.s);

MS m/e (FAB): 486 (75%), 356 (100%), 264 (98%);

Analysis calculated for C₂₉ H₃₁ N₃ O₄.0.25H₂ O: C, 71.07; H, 6.48; N,8.57%. Found: C, 71.08; H, 6.58; N, 8.40%.

EXAMPLE 41

4-Pyridinylmethyl 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!carbamate ##STR85##

To a stirred solution of ##STR86## (Veber, et al., J Org Chem1977;42:3256) (302 mg, 1.1 mmol) andα-methyltryptophanyl-1-phenethylamide (321 mg, 1 mmol) in DMF (10 mL,anhydrous) was added solid DMAP (122 mg, 1 mmol). After stirringovernight at room temperature, the DMF was removed at 60° C. underreduced pressure and the residue suspended between EtOAc (50 mL) and 1NNaOH solution (50 mL). The organic phase was washed with 5×30 mLportions of 1N NaOH solution, brine (30 mL), dried over MgSO₄. filtered,and solvent removed under reduced pressure. Residue chromatographedusing normal phase silica with EtOAc/MeOH/NH₃ (90:10:1) to obtaindesired product which crystallized from ether giving white needles (180g, 39%); mp 146°-148° C.;

α!_(D) ²⁰ =+4 (c=0.5, MeOH);

IR (film): 3309 (br, NH), 1721 (CDCl urethane), 1650 (CO, amide), 1609,1494, 1455, 1417, 1342, 1252, 1077, 910, 735, 700, 666 cm⁻ ;

NMR (CDCl₃): δ1.27 (3H, d, J=6.9 Hz, CH, CH₃); 1.67 (3H, s, CCH₃); 3.32(1H, d, J 14.7 Hz, one of CH₂ indole); 3.47 (1H, d, J=14.7 Hz, one ofCH₂ indole); 5.00 (1H, p, J=7.0 Hz, CH₃ CHNH); 5.07 (2H, s, CH₂ O); 6.20(1H, d, J=7.3 Hz CONHCH); 5.67 (1H, s, OCONH); 6.87 (1H, d, J=2.3 Hz,indole C₂ H); 7.05-7.30 (9H, m, CHPh, 2 indole CH's and 2 pyridyl CH's);7.36 (1H, d, J=3.0 Hz, indole C₇ H); 7.59 (1H, d, J=7.9 Hz indole C₄ H);8.09 (1H, s, indole NH); 8.54 (2H, d.d, J=4.4 and 1.6 Hz, pyridyl CH's);

MS m/e (CI⁺): 457 (M⁺ +H, 2%), 348 (5%), 244 (4%), 219 (1%), 201 (3%),138 (10), 130 (24%), 110 (100%), 92 (52%); Analysis calculated for C₂₇H₂₈ N₄ O₃.0.25H₂ O: C, 70.34; H, 6.23; N, 12.15%. Found: C, 70.31; H,6.08; N, 11.99%.

EXAMPLE 42

3-Thienylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR87## Step 1

To a stirred solution of 3-thiophenmethanol (1.14 g, 10 mmol) and4-nitrophenylchloroformate (2.01 g, 10 mmol) in dichloromethane (50 mL)at 0° C. was added dropwise a solution of pyridine (0.79 g, 10 mmol) indichloromethane (10 mL). Reaction mixture allowed to warm to roomtemperature overnight. Solvent removed under reduced pressure andresidue taken up between EtOAc (50 mL) and 10% citric acid solution (50mL). Organic phase washed successively with 10% citric acid solution(2×30 mL), H₂ O (30 mL), saturated NaHCO₃ solution (2×50 mL), and brine(50 mL). Organic phase dried over MgSO₄, filtered, and solvent removedunder reduced pressure. Two crystallizations from EtOAc gave pureproduct (1.11 g, 40%); mp 75.0°-78.4° C.;

IR (film): 1763 (C=0), 1593 (aromatic C--H), 1522 (NO₂), 1491, 1347(NO₂), 1211, 1164, 862 cm⁻¹ ;

NMR (CDCl₃): δ5.30 (2H, s, CH₂); 7.16-7.18 (1H, m, aromatic C--H);7.35-7.45 (2H, m, aromatic); 7.37 (2H, d, J=9.1 Hz, ##STR88## 8.27 (2H,d, J=9.2 Hz ##STR89##

Analysis calculated for C₁₂ H₉ NO₅ S: C, 51.61; H. 3.25; N, 5.02; S.11.48%. Found: C, 51.57; H. 3.21; N, 5.03; S, 11.34%.

Step 2

To a stirred solution of the carbonate (154 mg, 0.55 mmol) anda-methyltryptophanyl-1-phenethylamide (160 mg, 0.5 mmol) in DMF (5 mL,anhydrous) was added solid DMAP (61 mg, 0.5 mmol) and left to stirovernight at room temperature. Solvent removed at 60° C. under reducedpressure and the residue taken up in EtOAc (30 mL) and washedsuccessively with 10% citric acid solution (2×30 mL), H₂ O (30 mL), 1NNaOH (5×30 mL, until aqueous phase no longer intense yellow in color),and brine (2×30 mL). Organic phase dried over MgSO₄, filtered, solventremoved under reduced pressure, and residue crystallized from ether togive pure product (197 mg, 85%); mp 117°-121° C.;

IR (film): 3327 (br, NH), 1711 (CO, urethane), 1651 (CO, amide), 1494,1454, 1247, 1071, 909, 741 cm⁻¹ ;

NMR (CDCl₃): δ1.32 (3H, d, J=6.9 Hz, CH₃ CH); 1.61 (3H, s, CH₃ C), 3.25(1H, d, J=14.8 Hz, one of CH₂ indole); 3.46 (1H, d, J=15 Hz, one of CH₂indole); 4.95-5.15 (3H, m, CH₂ O and CHPh); 5.33 (1H, s, OCONH);6.35-6.45 (1H, br.d, CONHCH); 6.76 (1H, s, indole C₂ H); 7.05-7.35 (11H,m, aromatics); 7.57 (1H, d, J=7.7 Hz, indole C₄ -H); 8.01 (1H, s, indoleNH); MS m/e (Cl⁻): 462 (M⁺ +H, 0.2%), 348 (4%), 304 (2%), 244 (5%), 219(1%), 158 (1%), 130 (37%), 114 (94%), 97 (100%), 85 (71%);

Analysis calculated for C₂₆ H₂₇ N₃ O₃ S: C, 67.66; H, 5.90; N, 9.10; O,6.95%. Found: C, 67,51; H, 5.88; N, 9.03; O, 6.94%.

EXAMPLE 43

2-Thienylmethyl R-(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR90## Step 1

See Method as for Example 42. Yield=2.09 g, 75%; mp 67.5°-68.5° C.; IR(film): 1766 (CO, carbonate), 1616 and 1594 (aromatic CH); 1523 (NO₂);1493; 1347 (NO₂); 1248, 1213, 863 cm⁻¹ ;

NMR (CDCl₃): δ5.45 (2H, s, CH₂ O; 6.98-7.07 (1H, m, aromatic CH);7.18-7.25 (1H, m, aromatic CH); 7.30-7.43 (1H, m, aromatic CH); 7.38(2H, d, J=9.2 Hz, CH meta to NO₂); 8.28 (2H, d, J=9.2 Hz, CH ortho toNO₂);

Analysis calculated for C₁₂ H₉ NO₅ S: C, 51.61; H, 3.25; N, 5.02%.Found: C, 51.56; H, 3.20; N, 4.94%.

Step 2

See Method as for Example 42. Product chromatographed on normal phasesilica using 2% MeOH in CH₂ Cl₂ followed by crystallization from ethergave pure product (220 mg, 95%); mp 125°-127° C.;

α!_(D) ²⁰ =+5.7° (c=0.5 MeOH);

IR (film): 3327 (br, NH), 1713, 1651, 1494, 1456, 1247, 1068, 740, 699cm⁻¹ ;

NMR (CDCl₃): δ1.32 (3H, d, J=6.9 Hz, CH₃ CH); 1.62 (3H, s, CCH₃); 3.24(1H, d, J=14.7 Hz, one of CH₂ indole); 3.51 (1H, d, J=14.8 Hz, one ofCH₂ indole); 5.01 (1H, p, J=7.1 Hz, NHCHCH₃); 5.19 (1H, d, J=12.8 Hz,one of CH₂ O); 5.25 (1H, d, J=12.8 Hz, one of CH₂ O); 5.33 (1H, s,OCONH); 6.30-6.40 (1H, br.d, CONHCH); 6.77 (1H, s, indole C₂ H);6.93-7.30 (10H, m, aromatics); 7.33 (1H, d, J=8.0 Hz, indole C₇ -H);7.57 (1H, d, J=7.8 Hz, indole C₄ -H); 7.95 (1H, s, indole NH);

MS m/e (CI⁺): 462 (M⁺ +H, 0.2%), 461 (M⁺, 0.2%), 418 (2%), 348 (3%), 304(3%) , 244 (4%) , 191 (2%), 130 (30%), 114 (34%), 97 (100%), 85 (47%);

Analysis calculated for C₂₆ H₂₇ N₃ O₃ S: C, 67.66; H, 5.90; N, 9.10; S,6.95%. Found: C, 67.38; H, 5.82; N, 9.02; S, 7.08%.

EXAMPLE 44

2,3-Dihydro-1H-inden-3-yl R-(R*,S*)!-1(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(phenylethyl)amino!-ethyl!carbamate ##STR91## Step 1

See Method for Example 42. Product unstable on standing and unable toobtain a pure crystalline sample. A sample about 90% by NMR was used assoon as possible for Step 2.

Step 2

See Method for Example 42. Crude product chromatographed using normalphase silica using 1.5% MeOH in CH₂ Cl₂ then rechromatographed using 35%EtOAc in hexane to give pure product (1:1 mix of diastereoisomers, 30mg, 12%); mp 75°-80° C.;

α!_(D) ²⁰ =+13.8° (c=0.5 MeOH);

IR (film): 3331 (br, NH), 3057, 2976, 2935, 1705 (CO, urethane), 1653(CO, amide), 1494, 1458, 1376, 1341, 1248, 1070, 742, 700 cm⁻¹ ;

NMR (CDCl₃) mix of 2 diastereoisomers: δ1.31 (1.5H, CH₃ CH of onediastereoisomer, d, J=6.9 Hz); 1.39 (1.5H, d, J=6.9 Hz, CH₃ CH of onediastereoisomer); 1.61 and 1.62 (each 1.5H, each s, CH₃ C for bothdiastereoisomers); 2.00-2.10 (1H, m, CH of indane); 2.40-2.55 (1H, m, CHof indane); 2.80-2.90 (1H, m, CH of indole); 3.00-3.15 (1H, m, CH ofindole); 3.22 (0.5H, d, J=14.7 Hz, one of CH₂ indole for onediastereoisomer); 3.27 (0.5H, d, J=14.6 Hz, one of CH₂ indole for onediastereoisomer); 3.47 (0.5H, d, J=14.1 Hz, one of CH₂ indole for onediastereoisomer); 3.49 (0.5H, d, J=14.0 Hz, one of CH₂ indole for onediastereoisomer); 4.98-5.12 (1H, m, CHCH₃); 5.20 (1H, s, OCONH);6.10-6.15 (1H, m, CHOCO); 6.40-6.50 (1H, m, CONHCH); 6.80 and 6.84 (each0.5H, each s, each half of C₂ -H, indole); 7.05-7.43 (12H, m,aromatics); 7.59 (1H, d, J=8.0 Hz, indole C₇ -H); 7.96 and 8.00 (each0.5H, each s, each half of indole NH);

MS m/e (FAB): 5043 (M⁺ +Na, 20%), 482.3 (M⁺ +H, 12%), 4383 (4%), 366.2(55%), 322.2 (100%), 304.2 (36%);

Analysis calculated for C₃₀ H₃₁ N₃ O₃ : C, 74.82; H, 6.49; N, 8.73%.Found: C, 74.62; H, 6.46; N, 8.66%.

EXAMPLE 45

1-Naphthalenylmethyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR92## Step 1

See Method for Example 42. Crystallization of product from crude residueusing EtOAc followed by washing with 10% citric acid solution (2×30 mL)and multiple water washes gave pure product (2.37 g, 73%); mp150.5°-152.5° C.;

IR (film): 1752 (C═O), 1615, 1595 (aromatic C--H); 1536 (NO₂); 1360(NO₂); 1281 cm⁻¹ ;

NMR (DMSO-d₆): δ5.48 (2H, s, Ar CH₂ O; 7.50-7.65 (3H, m, aromatics CH);7.59 (2H, d, J=9.2 Hz, meta to NO₂ group); 7.90-8.05 (4H, m, aromaticCH); 8.32 (2H, d, J=9.1 Hz, ortho to NO₂ group);

Analysis calculated for C₁₈ H₃ NO₅ : C, 66.87; H, 4.05; N, 4.33%. Found:C, 66.74; H, 4.06; N, 4.27%.

Step 2

See Method for Example 45. Crude product chromatographed on normal phasesilica using 3% MeOH/CH₂ Cl₂ then crystallized from ether to give pureproduct (220 mg, 87%); mp 121°-122° C.;

α!_(D) ²⁰ =+21.2° (c=0.5, MeOH); IR (film): 3342 (br), 3052, 2924 and2926 (CH, str); 1717 (CO, urethane); 1653 (CO, amide); 1495, 1457, 1250,1073, 819, 742 cm⁻¹ ;

NMR (CDCl₃): δ1.28 (3H, d, J 6.9 Hz, CH₃ CH); 1.63 (3H, s, CH₃ C); 3.26(1H, d, J=14.7 Hz, one of CH₂ indole); 3.48 (1H, d, J=14.7 Hz, one ofCH₂ indole); 5.00 (1H, p, J=7.0 Hz, NHCHCH₃); 5.24 (1H, d, J=12.5 Hz,one of CH₂ O); 5.26 (1H, d, J=12.1 Hz, one of CH₂ O); 5.40 (1H, s,OCONH); 6.30-6.40 (1H, br.d, CONHCH); 6.74 (1H, s, indole C2-H);7.05-7.30 (7H, m, aromatics); 7.31 (1H, d, J=8.0 Hz, indole C7-H));7.40-7.52 (3H, m, aromatics); 7.58 (1H, d, J=8.4 Hz, indole C4-H));7.75-7.85 (5H, m, aromatics and indole NH);

MS m/e (FAB): 506.3 (M⁺ +H, 100%), 462.3 (5%), 429.1 (15%), 401.0 (14%),376.2 (18%) 341.4 (50%), 304.2 (54%), 281.1 (34%), 257.3 (34%);

Analysis calculated for C₃₂ H₃₁ N₃ O₃ : C, 76.02; H, 6.18; N, 8.31%.Found: C, 75.88; H, 6.19; N, 8.28%.

EXAMPLE 46

2,3-Dihydro-1H-inden-2-yl 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbanate ##STR93## Step 1

See Method for Example 42. Product crystallized from EtOAc and washedwith ether to give product (1.8 g, 60%); mp 110.5°-113.5° C.;

IR (film): 1765 (CO), 1616, 1594 (aromatic C--H); 1525, 1349 (NO₂);1261; 1226; 1187; 858 cm⁻¹ ;

NMR (DMSO-d₆): δ3.21 (2H, d.d, J=17 and 2.8 Hz CH_(A) H_(B) CHCH_(A)H_(B) ; 3.41 (2H, d.d, J=17 and 6.1 Hz, CH_(A) H_(B) CHCH_(A) H_(B));5.51-5.62 (1H, m, CHOCOO); 7.18-7.32 (4H, m, aromatic H); 7.37 (2H, d,J=9.2 Hz, H's meta to NO₂ group); 8.27 (2H, d, J=9.2 Hz, H's ortho toNO₂ group);

Analysis calculated for C₁₆ H₁₃ NO₅ : C, 64.21; H, 4.38; N, 4.68%.Found: C, 64.36; H, 4.38; N, 4.68%.

Step 2

See Method for Example 42. Used 180 mg (0.6 mmol) of carbonate. Crudeproduct chromatographed using normal phase silica using 2% MeOH/CH₂ Cl₂then crystallized from ether to give product (170 mg, 71%); mp 152°-157°C.;

α!_(D) ²² =+15.3° (c=1, MeOH);

IR (film): 3326 (br, NH str), 2924 and 2852 (CH, str), 1705 (COurethane), 1652 (CO, amide), 1494, 1457, 1252, 1073, 819, 741 cm⁻¹ ;

NMR (CDCl₃): δ1.35 (3H, d, J=6.9 Hz, CH₃ CH); 1.58 (3H, s, CCH₃);2.90-2.98 (2H, m, indane CH); 3.20-3.32 (3H, m, 2 indane CH and one ofCH₂ indole); 3.46 (1H, d, J=14.5 Hz, one of CH₂ indole); 5.02 (1H, p,J=6.9 Hz, NHCHCH₃); 5.20 (1H, s, OCONH); 5.38-5.48 (1H, m, CHOCONH);6.30-6.40 (1H, br.d, CONHCH); 6.87 (1H, s, indole, C₂ H); 7.10-7.35(12H, m, aromatic CH₃); 7.59 (1H, d, J=8.1 Hz, indole C₄ -H); 8.00 (1H,s, indole NH);

m/e (CI+): 482 (M⁺ +H, 6%), 348 (14%) , 304 (11%), 244 (12%), 145 (14%)134 (78%), 130 (72%), 117 (100%), 105 (88%) , 91 (24%);

Analysis calculated for C₃₀ H₃₁ N₃ O₃ : C, 74.82; H, 6.49; N, 8.73%.Found: C, 74.72; H, 6.50; N, 8.76%.

EXAMPLE 47

(2-Fluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-1-phenylethyl)amino!ethyl!carbamate ##STR94## Step 1

See Method for Example 42. Crude residue chromatographed using 10% EtOAcin hexane on normal phase silica then crystallized from ethyl acetate togive pure product (0.990 g, 34%); mp 84°-84.5° C.;

IR (film): 1752 (CO, carbonate), 1526 (NO₂), 758 cm⁻¹ ;

NMR (CDCl₃): δ5.38 (2H, s, PhCH₂); 7.08-7.23 (2H, m, aromatic CH);7.32-7.54 (2H, m, aromatic CH); 7.39 (2H, d, J=9.2 Hz, CH meta to NO₂);8.27 (2H, d, J=9.2 Hz, CH's ortho to NO₂);

Analysis calculated for C₁₄ H₁₀ NO₅ F: C, 57.73; H, 3.46; N, 4.81%.Found: C, 57.77; H, 3.52; N, 4.81%.

Step 2

See Method for Example 42 except used 174 mg (0.6 mmol) of carbonate.Crude product chromatographed on normal phase silica using 2% MeOH/CH₂Cl₂ then crystallized from ether to give pure product (96 mg, 41%); mp107°-111° C.;

α!_(D) ²² =+8° (c=0.25, MeOH);

IR (film): 3338 (br, NH), 1713 (CO, urethane); 1652 (CO, amide), 1494,1456, 1341, 1233, 1111, 1071, 909, 743 cm⁻¹ ;

NMR (CDCl₃): δ1.30 (3H, d, J=6.9 Hz, CH₃ CH); 1.62 (2H, s, CH₃ C); 3.26(1H, d, J=14.7 Hz, one of CH₂ indole); 3.47 (1H, d, J=14.9 Hz, one ofCH₂ indole); 5.01 (1H, p, J=7.1 Hz, NHCHCH₃); 5.13 (1H, d, J=12.5 Hz,one of CH₂ O); 5.19 (1H, d, J=12.8 Hz, one of CH₂ O); 5.38 (1H, s,OCONH); 6.35 (1H, d, J=7.6 Hz, NHCH); 6.81 (1H, d, J=2.2 Hz, indole C₂H); 7.00-7.38 (12H, m, aromatics); 7.58 (1H, d, J=7.8 Hz, indole C₄ -H);8.00 (1H, s, indole NH);

MS m/e (CI⁺): 474 (M⁺ +H, 5%), 348 (20%), 347 (10%), 304 (9%) , 281(8%), 244 (32%), 219 (8%), 199 (9%), 158 (9%), 131 (23%), 130 (100%),109 (57%), 105 (27%), 97 (16%);

Analysis calculated for C₂₈ H₂₈ N₃ O₃ F: C, 71.02; H, 5.96; N, 8.87%.Found: C, 71.16; H, 6.01; N, 8.87%.

EXAMPLE 48

3-Furanylmethyl R-(R*,S*)!- 1(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR95## Step 1

See Method for Example 42. Product chromatographed using 14%EtOAc/Hexane then crystallized from EtOAc to give pure product (1.87 mg,71%); mp 56.5°-57.5° C.;

IR (film): 1766 (CO, carbonate), 1617, 1594, 1525, 1348 (NO₂), 1214,1161, 863 cm⁻¹ ;

NMR (CDCl₃): δ5.18 (2H, s, PhCH₂); 6.51 (1H, d, J=1.1 Hz, furan C₄ -H);7.37 (2H, d, J=9.2 Hz, CH meta to NO₂); 7.45 (1H, s, furan C₂ or C₅ -H);7.57 (1H, s, furan C₂ or C₅ -H); 8.27 (2H, d, J=9.2 Hz, CH ortho toNO₂);

Analysis calculated for C₁₂ H₉ NO₆ : C, 54.76; H, 3.45; N, 5.32%. Found:C, 54.68; H, 3.45; N, 5.32%.

Step 2

See Method for Example 42 except used 158 mg (0.6 mmol) of carbonate.Crude product chromatographed using normal phase silica with 1% MeOHn-dichloromethane as eluent then crystallized from ether to give product(164 mg, 74%); mp 126°-128° C.;

α!_(D) ²¹ =+4.9° (c=1, MeOH);

IR (film): 3332 (br, NH), 1709 (CO, urethane), 1652 (CO, amide), 1495,1456, 1247, 1066, 1020, 874, 742 cm⁻¹ ;

NMR (CDCl₃): δ1.32 (3H, d, J=6.9 Hz, CHCH₃); 1.61 (3H, s, CCH₃); 3.25(1H, d, J=14.7 Hz, one of CH₂ indole); 3.45 (1H, d, J=14.8 Hz, one ofCH₂ indole); 4.93 (2H, s, CH₂ O); 5.02 (1H, p, J=7.2 Hz, NHCHCH₃); 5.32(1H, s, OCONH); 6.30-6.40 (1H, m, CHNH); 6.37 (1H, s, furan C₄ -H); 6.81(1H, d, J=2.2 Hz, indole C₂ H); 7.05-7.35 (9H, m, aromatics); 7.43 (1H,s, furan CH); 7.58 (1H, d, J=7.8 Hz, indole C₄ -H); 8.02 (1H, s, indoleNH);

MS m/e (CI⁺): 446 (M⁺ +1, 7%), 445 (2%), 402 (12%), 316 (11%), 304(26%), 253 (12%), 244 (6%), 199 (8%), 191 (10%), 131 (23%), 130 (100%),105 (51%), 81 (34%);

Analysis calculated for C₂₆ H₂₇ N₃ O₄ : C, 70.10; H. 6.11; N, 9.43%.Found: C, 70.13; H, 6.13; N, 9.46%.

EXAMPLE 49

2-Furanylmethyl R,(R*,S*)!- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR96## Step 1

See Method for Example 42, however, product was unstable and no puresample was obtained. Used in the next step after chromatography onnormal phase silica using 12.5% EtOAc/Hexane estimated purity >90%;

NMR (CDCl₃): δ5.26 (2H, s, CH₂ O); 6.37-6.45 (1H, m, H₄ on ring); 6.54(1H, d, J=3.2 Hz, H₃ on ring); 7.38 (2H, d, J=9.2 Hz, H meta to NO₂Group); 7.43-7.50 (1H, m, H₅ on ring); 8.27 (2H, d, J=9.1 Hz, H ortho toNO₂ group);

Step 2

See Method for Example 42 except used 158 mg (0.6 mmol) of carbonate.Crude product chromatographed on normal phase silica using 1% MeOH/CH₂Cl₂ then crystallized from ether to give product (95 mg, 43%); mp133°-140.5° C.;

α!_(D) ²¹ =+9.0° (c=0.5, MeOH);

IR (film): 3331 (br, NH), 1713 (CO, urethane), 1652 (CO, amide), 1495,1248, 1068, 742 cm⁻¹ ;

NMR (CDCl₃): δ1.33 (3H, d, J 6.9 Hz, CHCH₃); 1.61 (3H, s, CCH₃); 3.24(1H, d, J=14.7 Hz, one the CH₂ indole); 3.46 (1H, d, J=14.8 Hz, one ofCH₂ indole); 4.95-5.10 (3H, m, CH₂ O and CONHCH); 5.31 (1H, s, OCONH);6.30-6.40 (3H, m, CONHCH, furan C₃ and C₄ -H); 6.80 (1H, d, J=7.2 Hz,indole C₂ H); 7.05-7.35 (8H, m, aromatics); 7.38 (1H, s, furan C₅ -H);7.57 (1H, d, J=8.1 Hz, indole C₄ -H); 7.99 (1H, s, indole NH);

MS m/e (CI⁺ : 446 (M⁺ +1, 23%), 445 (M⁺, 11%), 402 (66%), 348 (16%), 316(16%), 304 (82%), 253 (22%), 244 (24%), 191 (36%), 130 (100%), 105(88%), 81 (49%);

Analysis calculated for C₂₆ H₂₇ N₃ O₄ : C, 70.10; H, 6.11; N, 9.43%.Found: C, 70.09; H, 6.16; N, 9.37%.

EXAMPLE 50

(3-Fluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR97##

To a stirred solution of 3-fluorobenzyl alcohol (189 mg, 1.5 mmol) andtriphosgene (178 mg, 0.6 mmol) under an atmosphere of N₂ at 0° C. (icebath) in CH₂ Cl₂ (10 mL, anhydrous) was added a solution of pyridine(119 mg, 1.5 mmol) in CH₂ Cl₂ (2 mL, anhydrous). IR recorded after 5 and30 minutes indicated no change with chloroformate at 1776 cm⁻¹. Solventremoved under vacuum at 30° C. using a 20% NaOH trap for excessphosgene, added EtOAc (20 mL), and filtered of pyridine hydrochloride.Removed solvent under reduced pressure and added about half ofchloroformate to a stirred solution of α-metryptophanyl-1-phenethylamide (160 mg, 0.5 mmol) and pyridine (40 mg, 0.5 mmol) in THF (20 mL,anhydrous). Precipitate formed immediately and after 5 minutes H₂indicated no starting amine remaining. Removed solvent under reducedpressure and added 50 mL of EtOAc. Organic phase washed successivelywith 10% citric acid solution (2×30 mL)), H₂ O (30 mL), saturated NaHCO₃(2×30 mL), H₂ O (2×30 mL), brine (30 mL), then dried over MgSO₄. Productrecrystallized from ether to give pure product (0.2 g, 84%); mp109°-112.5° C.;

α!_(D) ²¹° C. =+8.5° (c=1, MeOH);

IR (film): 3334 (br, NH str), 1717 (CO, urethane), 1653 (CO, amide);1592, 1491, 1456, 1256, 1070, 744 cm⁻¹ ;

NMR (CDCl₃): δ1.29 (3H, d, J=6.9 Hz, CH₃ CH); 1.63 (3H, s, CH₃ C); 3.27(1H, d, J=14.8 Hz, one of CH₂ indole); 3.46 (1H, d, J=14.6 Hz, one ofCH₂ indole); 4.95-5.05 (1H, m, NHCHCH₃); 5.05 (2H, s, CH₂ O); 5.46 (1H,s, OCONH); 6.29 (1H, d, J=7.3 Hz, CONHCH); 6.81 (1H, s, indole C₂ -H);6.95-7.30 (11H, m, aromatics); 7.34 (1H, d, J=8.0 Hz, indole C₇ -H);7.58 (1H, d, J=7.9 Hz, indole C₄ -H); 8.01 (1H, s, indole NH); MS m/e(CI⁺): 475 (M⁺, 2.27%), 474 (M⁺ +H, 85%); 473 (M⁺, 13%); 353 (12%); 348(14%); 348 (14%); 344 (28%); 305 (16%); 304 (67%); 281 (29%); 244 (23%);199 (14%); 131 (44%); 130 (100%);

Analysis calculated for C₂₈ H₂₈ N₃ O₃ F: C, 71.02; H, 5.96; N, 8.87%.Found: C, 71.01; H. 6.00; N, 8.87%.

EXAMPLE 51

(4-Fluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR98##

See Method for Example 50. Crystallization from ether gave pure product(191 mg, 81%); mp 101°-111° C.;

α!_(D) ²¹ =+7.9 (c=0.5, MeOH);

IR (film): 3327 (br, NH str), 1716 (CO, urethane), 1653 (CO, amide),1511, 1457, 1225, 1071, 825, 743 cm⁻¹ ;

NMR (CDCl₃): δ1.29 (3H, d, J=6.9 Hz, CH₃ CH); 1.62 (3H, s, CH₃ C); 3.26(1H, d, J=14.8 Hz, one of CH₂ indole); 3.46 (1H, d, J=14.8 Hz, one ofCH₂ indole); 4.95-5.05 (1H, m, CONCHCH₃); 5.02 (2H, s, CH₂ O); 5.39 (1H,S, OCONH); 6.25-6.35 (1H, br.d, CONHCH); 6.80 (1H, s, indole C₂ -H);6.95-7.30 (1H, m, aromatics); 7.34 (1H, d, J=7.8 Hz, indole C₇ -H); 7.58(1H, d, J=7.9 Hz, indole C₄ -H); 7.99 (1H, s, indole NH); MS m/e (CI⁺) :475 (M⁺ +2, 22%), 474 (M⁺ +H, 68%), 473 (M⁺, 10%), 430 (35%), 348 (29%),344 (31%), 305 (22%), 304 (83%), 281 (23%), 244 (36%), 131 (60%), 130(100%); Analysis calculated for C₂₈ H₂₈ N₃ O₃ F: C, 71.02; H, 5.96; N,8.87%. Found: C, 70.80; H, 5.93; N, 8.69%.

EXAMPLE 52

(2,3-Difluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-methyl)-1-methyl-2-oxo-(1-phenylethyl)amino!ethyl!carbamate ##STR99##

See method for Example 50. Crude product chromatographed using 2%MeOH/CH₂ Cl₂ the crystallized from ether to give pure product (232 mg,94%); mp 96°-102° C.;

α!_(D) ²¹ =+6.7° (c=0.5, MeOH);

IR (film): 3336 (br, NH str), 1716 (CO, urethane), 1652 (CO, amide),1492, 1457, 1288, 1250, 1069, 741 cm⁻¹ ;

NMR (CDCl₃): δ1.29 (3H, d, J=6.9 Hz, CH₃ CH); 1.60 (3H, S, CCH₃); 3.27(1H, d, J=14.7 Hz, one of CH₂ indole); 3.46 (1H, d, J=14.6 Hz, one ofCH₂ indole); 4.95-5.05 (1H, m, NHCHCH₃); 5.13 (1H, d, J=13.0 Hz, one ofCH₂ O); 5.18 (1H, d, J=13.4 Hz, one of CH₂ O); 5.49 (1H, s, OCONH); 6.29(1H, d, J=7.2 Hz, NHCH); 6.84 (1H, s, indole C₂ H); 6.95-7.35 (11H, m,aromatics); 7.58 (1H, d, J=7.7 Hz, indole C₄ -H); 8.10 (1H, s, indoleNH);

MS m/e (CI⁺): 493 (M⁺ +2, 10%), 492 (M⁺ +1, 4%), 491 (M⁺, 5%), 371(11%), 348 (19%), 305 (17%), 304 (54%), 299 (18%), 244 (22%), 199 (12%),144 (40%), 130 (98%), 127 (100%), 105 (78%);

Analysis calculated for C₂₈ H₂₇ N₃ O₃ F₂ : C, 68.42; H, 5.54; N. 8.55%.Found: C, 68,43; H, 5.64; N, 8.51%.

EXAMPLE 53

(2,4-Difluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR100##

See Method for Example 50. Crude product chromatographed using 2%MeOH/CH₂ Cl₂ then crystallized from ether to give pure product (240 mg,98%);

mp 77°-87° C.;

α!_(D) ²¹ =+5.6 (c=1, MeOH);

IR (film): 3332 (br, NH str), 1713 (CO, urethane), 1651 (CO, amide),1507, 1250, 1140, 1101, 1071, 742 cm⁻¹ ;

NMR (CDCl₃): δ1.29 (3H, d, J=6.9 Hz, CH₃ CH); 1.03 (3H, s, CCH₃); 3.27(1H, d, J=14.7 Hz, one of CH₂ indole); 3.46 (1H, d, J=14.9 Hz, one ofCH₂ indole); 4.95-5.05 (1H, m, CHCH₃); 5.09 (2H, s, CH₂ O); 5.43 (1H, s,OCONH); 6.23-6.33 (1H, br.d, CONHCH); 6.75-6.90 (3H, m, aromatics);7.05-7.35 (9H, m, aromatics); 7.58 (1H, d, J=7.8 Hz, indole C₄ -H); 8.01(1H, s, indole NH);

MS m/e (CI⁺) : 493 (M⁺ +2, 11%) , 492 (M⁺ +1, 40%) , 491 (M⁺, 7%), 448(12%), 361 (26%), 348 (15%), 304 (56%), 299 (15%), 244 (33%), 199 (14%),144 (36%), 131 (45%), 130 (100%) , 127 (93%) , 105 (70%);

Analysis calculated for C₂₈ H₂₇ N₃ O₃ F₂ : C, 68.42; H, 5.54; N, 8.55%.Found: C, 68.66; H, 5.63; N, 8.45%.

EXAMPLE 54

(2,5-Difluorophenyl)methyl R-(R*,S*)!-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR101##

See Method for Example 50. Crystallization from ether gave pure product(229 mg, 95%); mp 121°-122° C.;

α!_(D) ²¹ =+6.0 (c=0.5, MeOH);

IR (film): 3336 (br, NH str), 1721 (CO, urethane), 1656 (CO, amide),1496, 1457, 1246, 1191, 1144, 1072, 909, 741 cm⁻¹ ;

NMR (CDCl₃): δ1.29 (3H, d, J=6.9 Hz, CH₃ CH); 1.64 (3H, s, CCH₃); 3.28(1H, d, J=14.7 Hz, one of CH₂ indole); 3.47 (1H, d, J=14.0 Hz, one ofCH₂ indole); 4.95-5.05 (1H, m, NHCHCH₃); 5.08 and 5.14 (each 1H, each d,each one of CH₂ O, J=13.4 Hz); 5.51 (1H, s, OCONH); 6.28 (1H, d, J=7.6Hz, CONHCH); 6.85 (1H, d, J=2.1 Hz, indole C₂ H); 6.90-7.33 (10H, m,aromatics); 7.34 (1H, d, J=8.0 Hz, indole C₇ -H); 7.58 (1H, d, J=7.8 Hz,indole C₄ -H); 8.05 (1H, s, indole NH);

MS m/e (CI⁺): 493 (M⁺ +2, 14%), 492 (M⁺ +1, 55%), 491 (M⁺, 6%), 362(12%), 348 (31%), 347 (17%), 304 (39%), 244 (40%), 131 (50%), 130(100%), 127 (65%), 105 (66%); Analysis calculated for C₂₈ H₂₇ N₃ O₃ F₂ :C, 68.42; H, 5.54; N, 8.55%. Found: C, 68.17; H, 5.46; N, 8.35%.

EXAMPLE 55

Phenylmethyl R-(R*,S*)! and S-(R*,R*)!--1-(1H-indazol-3-ylmethyl-)-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR102## Step 1:N-Benzyloxycarbonyltryptazan

A mixture of tryptazan (PD 018111) (0.09 g, 0.44 mmol), sodium hydrogencarbonate (0.13 g, 1.55 mmol), dibenzyldicarbonate (0.18 g, 0.63 mmol),water (5 mL), and dioxan (5 mL) was stirred at room temperatureovernight. The mixture was diluted with water, washed twice with ether,acidified with 1N hydrochloric acid, and extracted with ethyl acetate.The combined extracts were washed with water, dried over MgSO₄,filtered, and evaporated to dryness. Recrystallization from ethylacetate/hexane gave colorless crystals (0.12 g).

Step 2: Phenylmethyl R-(R*,S*)! and S-(R*,R*)!--1-(1H-indazol-3-ylmethyl-)-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate

To a solution of N-benzyloxycarbonyl tryptazan (0.12 g, 0.35 mmol) inethyl acetate (20 mL) was added hydroxybenzotriazole hydrate (0.058 g,0.38 mmol) followed by dicyclohexylcarbodiimide (0.075 g, 0.36 mmol).After stirring at room temperature for 3 hours, the mixture was filteredand (S)-α-methylbenzylamine (0.055 g, 0.45 mmol) in ethyl acetate (5 mL)was added to the filtrate. After stirring at room temperature overnight,the reaction mixture was washed with saturated sodium bicarbonatesolution, 1N hydrochloric acid, and water. The solution was then driedover magnesium sulphate, filtered, and evaporated to dryness. Theresidue was purified by reverse phase chromatography eluting withmethanol/water mixtures to give the title compound (0.070 g, 45%); mp116°-120° C.; NMR (300 MHz, CDCl₃): δ1.23 (3H, d, J=6.9 Hz); 3.32 (1H,dd, J=15.0, 7.3 Hz); 3.59 (1H, ddd, J=15.0, 9.7, and 4.8 Hz); 4.70-4.80(1H, m); 4.85-4.95 (1H, m); 5.11 (2H, s); 6.14 (0.5H d, J=7.4 Hz); 6.20(0.5H, d, J=7.1 Hz); 6.60-6.85 (1H, m); 6.90-7.40 (14H, m); 7.70-7.80(1H, m);

Analysis calculated for C₂₆ H₂₆ N₄ O₃ : C, 70.57; H, 5.92; N, 12.66%.Found: C, 70.41; H, 5.97; N. 12.60%.

EXAMPLE 56

Phenylmethyl R-(R*,S*)! and S-(R*,R*)!- 1-(5-fluoro-1H-indol-3-yl)methyl!-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR103## Step 1:N-Benzyloxycarbonyl-5-fluoro-RS-tryptophan

Dibenzyldicarbonate (0.39 g, 3.1 mmol) was dissolved in dioxan (15 mL)and added to a stirred suspension of 5-fluoro tryptophan (0.58 g, 2.6mmol) and sodium bicarbonate (0.67 g, 8.0 mmol) in water (15 mL). Afterstirring at room temperature overnight, the reaction mixture was dilutedwith water and washed with ether twice, acidified with 1N hydrochloricacid, and extracted three times with ethyl acetate. The combinedextracts were washed with water, dried MgSO₄, sulphate, filtered, andevaporated. Recrystallization from ethyl acetate and hexane gavecolorless crystals (0.75 g, 81%); mp 126°-128° C.;

NMR (300 MHz, DMSO-d₆): δ2.96 (1H, dd, J=14.4 and 9.6 Hz); 3.14 (1H, dd,J=14.5 and 4.4 Hz); 4.15-4.25 (1H, m); 4.97 (2H, s); 6.90 (1H, dt, J=9.2and 2.5 Hz); 7.10-7.35 (8H, m); 7.55 (1H, d, J=8.1 Hz); 10.94 (1H, s);12.6 (1H, bs);

Analysis calculated for C₁₉ H₁₇ FN₂ O₄ : C, 64.04; H, 4.81; N, 7.86.Found: C, 64.02; H, 4.80; N, 7.84.

Step 2: Phenylmethyl R-(R*,S*)! and S-(R*,R*)!- 1-(5-fluoro-1H-indol-3-yl)methyl!-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate

To a solution of N-benzyloxycarbonyl-5-fluorotryptophan (0.15 g, 0.42mmol) in ethyl acetate (25 mL) was added 1-hydroxybenzotriazole hydrate(0.066 g, 0.43 mmol) followed by dicyclohexylcarbodiimide (0.089 g, 0.43mmol). After stirring at room temperature for 2 hours, the mixture wasfiltered and to the filtrate was added a solution of(S)-α-methylbenzylamine (0.065 g, 0.54 mmol) in ethyl acetate (5 mL).After stirring at room temperature for 48 hours, the solution was washedwith saturated sodium bicarbonate solution, 1N hydrochloric acidsolution, and water. After drying over magnesium sulphate, the solutionwas filtered, dried, and evaporated. The residue was purified by reversephase chromatography to give the title compound (0.15 g, 78%); mp152°-155° C.;

NMR (300 MHz, CDCl₃): δ1.18 (1.5H, d, J=6.9 Hz); 1.32 (1.5H, d, J=6.9Hz); 3.00-3.15 (1H, m); 3.20-3.35 (1H, m); 4.35-4.50 (1H, m); 4.90-5.05(1H, m); 5.10 (2H, s); 5.35-5.50 (1H, m); 5.70-5.80 (1H, m); 6.78 (0.5H,d); 6.90-7.05 (3.5H, m); 7.20-7.35 (1OH, m); 7.80 (0.5H, s); 8.02 (0.5H,s);

Analysis calculated for C₂₇ H₂₆ FN₃ O₃ : C, 70.57; H, 5.70; N, 9.14%.Found: C, 70.67; H, 5.67; N, 9.09%.

EXAMPLE 57

Phenylmethyl 1-(1-methyl-1H-indol-3-ylmethyl!-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR104## Step 1:CBZ-1-methyl-DL-tryptophan

1-Methyl-DL-tryptophan was suspended in H₂ O/dioxan (20 mL) and NaHCO₃(0.072 g, 8 mmol) added. A solution of dibenzyldicarbonate (1.37 g, 4.8mmol) was added and the reaction was stirred at room temperatureovernight. The solution was diluted with water then washed with ether.The aqueous was then acidified to pH 1 with concentrated HCl andextracted with ethylacetate. The combined organic extracts were washedwith water, dried over MgSO₄, and the solvent removed in vacuo. Thebrown oil obtained was purified by reverse phase chromatography (0.800g, 65%); mp 58°-60° C.;

α!_(D) ²⁰ =0 (c=0.25, MeOH);

IR (film): 1716 (urethane CO), 1507 cm⁻¹ (amide II);

NMR (DMSO-d₆): δ2.99 (1H, dxd, J=14.7, 9.5 Hz, one of βCH₂); 3.16 (1H,dxd, J=14.7 and 4.5 Hz, one of βCH₂); 3.71 (3H, s, NCH₃); 4.32 (1H, m,αCH); 4.97 (2H, s, CH₂ Ph); 7.01-7.65 (11H, m, aromatic protons,urethane NH); 12.65 (1H, s, br, CO₂ H);

MS m/e (CI): 353 MH⁺ ;

Analysis calculated for C₂₀ H₂₀ N₂ O₄ : C, 68.17; H, 5.72; N. 7.95%.Found: C, 67.80; H, 5.86; N, 8.19%.

Step 2: CBZ-1-Methyl-DL-tryptophan-(+)-α-methylbenzylamine

CBZ-1-methyl-DL-tryptophan (0.39 g, 1.2 mmol), HBTU (0.91 g, 1.2 mmol),and diisopropylethylamine (0.42 mL, 2.4 mmol) were dissolved in DCM (3mL) and the solution stirred for 10 minutes at room temperature. The(±)-α-methylbenzylamine (0.15 mL, 1.2 mmol) was added and the reactionwas stirred for a further 4 hours. The solvent was removed in vacuo andthe resulting residue redissolved in ethylacetate. The organic waswashed with 5% HCl, 5% NaHCO₃, water, and brine. The organic layer wasthen dried over MgSO₄ and the solvent removed in vacuo. The crudematerial was purified by medium pressure chromatography,ethyl-acetate/hexane (0.076 g, 14%); mp 69.5°-71.8° C.;

α!_(D) ²⁰ =0 (c=0.25, MeOH);

IR (film): 1712 (urethane CO), 1687 (urethane CO), 1652 (amide I), 1548cm⁻¹ (amide II);

NMR (DMSO-d₆): δ1.23, 1.34 (3H, 2xd, J=6.9 and 7.5 Hz, CH₃); 2.84-3.19(2H, m, βCH₂); 3.66; 3.71 (3H, 2xs, N--CH₃); 4.32-4.37 (1H, m, CH);4.86-4.97 (3H, m, PhCH₂, CH); 6.87-7.66 (16H, m, Ph×2, indole aromatics,urethane NH); 8.32-8.41 (1H, 2xd, J=7.7 and 7.9 Hz, amide NH);

MS m/e (CI): 456.3 MH⁺ ;

Analysis calculated for C₂₈ H₂₉ N₃ O₃ : C, 73.82; H, 6.42; N, 9.22%.Found: C, 73.89; H, 6.57; N, 8.95%.

EXAMPLE 58

Phenylmethyl R-(R*, S*)!- 1-(2-naphthalenylmethyl-2-oxo-2-(1-phenylmethyl)amino!ethyl!carbamate ##STR105## Step 1:CBZ-D-3-(1-naphthyl)alanine

See Method for CBZ-1-methyl-DL-tryptophan in Example 57 (0.17 g, 22%);

IR (film): 1709 (urethane CO), 1532 cm⁻¹ (amide II);

NMR (DMSO-d₆): δ2.97-3.23 (2H, m, βCH₂); 4.32 (1H, m, αCH); 4.94 (2H, s,PhCH₂); 7.21-7.89 (13H, m, aromatics, urethane NH).

Step 2: CBZ-D-3-(2-naphthyl)alanine-3-(-)-α-methylbenzylamine

See Method as for the 1-methyl-DL-tryptophan derivative (0.081 g, 14%);mp 100.2°-102.7° C.;

α!_(D) ²⁰ =-26° (c=0.25, MeOH);

IR (film): 1709 (urethane CO), 1656 (amide I), 1537 cm⁻¹ (amide II);

NMR (DMSO-d₆): δ1.24 (3H, d, J=7.0 Hz, CH₃); 2.97 (1H, dxd, J=13.4 and9.9 Hz, one of βCH₂); 3.13 (1H, dxd, J=13.4 and 5.0 Hz, one of βCH₂);4.42 (1H, m, αH, methylbenzylamine); 4.89 (3H, m, PhCH₂, αCH); 7.23-7.48(14H, m, naphthyl H₃,6,7, Phx2, urethane NH); 7.84 (4H, m, naphthylH₁,4,5,8); 8.38 (1H, d, J=8.0 Hz, amide NH);

MS m/e (CI): 453 MH⁺ ;

Analysis calculated for C₂₉ H₂₈ N₂ O₃ : C, 76.34; H, 6.41; N, 6.36%.Found: C, 76.74; H, 6.22; N, 6.06%.

EXAMPLE 59

1-Phenylethyl N- (phenylmethoxy)carbonyl!-DL-tryptophan ##STR106##

To a solution of N-benzyloxycarbonyl-RS-tryptophan (1.07 g, 3.16 mmol),(S)-sec-phenethyl alcohol (0.39 g, 3.19 mmol) and dimethylaminopyridine(0.04 g, 0.33 mmol) in ethyl acetate (60 mL) was addeddicyclohexylcarbodiimide (0.65 g, 3.16 mmol). After stirring at roomtemperature overnight, the mixture was filtered and evaporated todryness. Purification by column chromatography eluting with 2% ethylacetate in dichloromethane gave a colorless gum (1.1 g, 79%); NMR (300MHz, CDCl₃): δ1.41 and 1.49 (3H, two d, J=6.5 Hz); 3.10-3.30 (2H, m);4.70-4.80 (1H, m); 5.00-5.15 (2H, m); 5.20-5.35 (1H, m); 5.80-5.95 (1H,two m); 6.49 and 6.89 (1H, two s); 7.00-7.35 (13H, m); 7.42 (0.5H, d,J=8.0 Hz); 7.55-7.60 (0.5H, m); 7.81-7.94 (1H, two s);

Analysis calculated for C₂₇ H₂₆ N₂ O₄ : C, 73.29; H, 5.92; N, 6.33%.Found: C, 73.03; H. 6.01; N, 6.21%.

EXAMPLE 60

Phenylmethyl 1-(benzo b!thien-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!carbamate ##STR107## Step 1: MethylN-CBz-α-methyl-3-benzothiophenylalanine

A solution of methyl α-methyl-3-benzothiophenylalanine (Horwell, et al.,W09204025 Al. Mar. 19, 1992) (0.5 g, 2.0 mmol), sodium hydrogencarbonate (0.50 g, 6.00 mmol), dibenzyldicarbonate (0.7 g, 2.4 mmol),water (10 mL), and dioxan (10 mL) was stirred at room temperatureovernight. The reaction mixture was diluted with water and ether. Theorganic phase was separated, washed with water, dried over MgSO₄,filtered, and evaporated to dryness. Purification by columnchromatography eluting with 2% ethyl acetate in dichloromethane gave anoil (0.6 g, 78%);

NMR (300 MHz, CDCl₃): δ1.68 (3H, s); 3.48 (1H, d, J=14.5 Hz); 3.60-3.75(4H, m); 5.05-5.20 (2H, m); 5.53 (1H, bs); 6.94 (1H, s); 7.20-7.40 (7H,m); 7.65-7.75 (1H, m); 7.80-7.85 (1H, m);

Analysis calculated for C₂₁ H₂₁ NO₄ S: C, 65.78; H, 5.52; N, 3.65%.Found: C, 65.85; H, 5.50; N, 3.49%.

Step 2: N-CBZ-α-methyl-3-benzothiophenylalanine

A solution of methyl N-CBZ-α-methyl-3-benzothiophenylalanine (0.6 g,1.57 mmol), lithium hydroxide hydrate (0.14 g, 3.33 mmol) in water (20mL), and dioxan (20 mL) was stirred at room temperature overnight. Thereaction mixture was diluted with water, washed with ether, acidifiedwith 1N hydrochloric acid, and extracted with ethyl acetate three times.The combined extracts were washed with water, dried over magnesiumsulphate, filtered, and evaporated to dryness. Crystallization fromether/hexane gave colorless crystals 0.48 g (83%); mp 133°-135° C.;

NMR (300 MHz, CDCl₃): δ1.28 (3H, s); 3.27 (1H, d, J=14.4 Hz); 3.59 (1H,d, J=14.4 Hz); 5.02 (1H, d, J 12.6 Hz); 5.08 (1H, d, J=12.3 Hz);7.25-7.40 (8H, m); 7.75 (1H, d, J=7.9 Hz); 7.90-8.00 (1H, m); 12.6 (1H,s);

Analysis calculated for C₂₀ H₁₉ NO₄ S: C, 65.02; H, 5.15; N, 3.79%.Found: C, 64.99; H, 5.15; N, 3.80%.

Step 3: Phenylmethyl 1- (benzob!thien-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!-carbamate

To a solution of N-CBZ-α-methyl-3-benzothiophenylalanine (0.12 g, 0.33mmol) in ethyl acetate (10 mL) was added hydroxybenzotriazole hydrate(0.055 g, 0.36 mmol) and followed by dicyclohexylcarbodiimide (0.072 g,0.35 mmol). After stirring at room temperature for 15 minutes, themixture was filtered and (S)-sec-phenylethylamine (0.051 g, 0.42 mmol)in ethyl acetate was added to the filtrate. After stirring at roomtemperature overnight, the mixture was diluted with ethyl acetate andwashed with saturated sodium hydrogen carbonate solution, 1Nhydrochloric acid solution and water. The solution was dried overmagnesium sulphate, filtered, and evaporated to dryness. Purification bycolumn chromatography eluting with dichloromethane/ethyl acetate 98:2and crystallization from ether gave colorless crystals (0.09 g, 58%); mp147°-150° C.;

NMR (300 MHz, DMSO-d₆): δ1.20-1.40 (6H, m); 3.30-3.60 (2H, m); 4.85-4.95(1H, m); 5.05 (2H, s); 7.00-7.40 (14H, m); 7.75-7.90 (1H, m); 7.90-7.95(1H, m); 8.0 and 8.1 (1H, two d).

EXAMPLE 61

Phenylmethyl R-(R*,R*)!--(4,5-dihydro-4-phenyl-2-thiazoly-1)-2-(1H-indol-3-yl)-1-methylethyl!carbamate##STR108##

A solution of Z-α-Me-R-tryphophanyl-R-phenylglycinol (0.14 g, 0.30 mmol)in toluene (20 mL) was treated with Lawesson's reagent (0.2 g, 0.5 mmol)and the mixture heated at reflux for 90 minutes. The crude reactionmixture was loaded onto a silica gel column and eluted with CH₂ Cl₂,then Et₂ O. Further purification was then carried out using reversephase silica gel and 85% MeOH in H₂ O as eluant to give the product as awhite foam (0.08 g, 57%); mp 64°-66° C.;

α!_(D) ²⁰ =-3° (c=0.25, MeOH);

IR (film): 3391, 1715, 1617, 1496, 1456 cm⁻¹ ;

NMR (DMSO-d₆): δ1.41 (3H, s); 2.94 (1H, br.t); 3.30 (1H, obscured by H₂O); 3.54 (1H, d, J=13.9 Hz); 3.71 (1H, br.t); 5.09 (2H, m); 5.46 (1H,m); 6.92 (1H, t, J=7.1 Hz); 7.00-7.39 (13H, m); 7.53 (1H, d, J=7.8 Hz);7.58 (1H, br.s); 10.92 (1H, br.s);

Analysis calculated for C₂₈ H₂₇ N₃ O₂ S.0.25H₂ O: C, 70.93; H. 5.85; N,8.86%. Found: C, 70.93; H, 5.73; N, 8.84%.

EXAMPLE 62 (See Scheme X)

Phenylmethyl 1-(cyanomethyl)-1-(1H-indol-3-ylmethyl)-2-oxo-2-(1-phenylethyl)amino!-ethyl!carbamate ##STR109## Step 1

RS-Tryptophanmethylester (2.03 g, 9.30 mmol) was stirred and dissolvedin formic acid (15 mL) at room temperature. To this was added aceticanhydride (4.4 mL, 46.5 mmol) in one portion and the mixture stirred for2.5 hours. The solution was poured into water (100 mL) and the mixtureneutralized by the addition of Na₂ CO₃. The product was extracted intoEtOAc (2×100 mL) and the combined extracts washed with saturated NaHCO₃solution (50 mL) and once with brine (50 mL). The EtOAc solution wasdried over MgSO₄, filtered, and the solvent removed in vacuo to give theproduct as a syrup. This was crystallized from 50% EtOAc/50% n-hexane asa white solid (1.55 g, 68%); mp 113°-119° C.;

IR (film): 3370, 2920, 1740, 1672, and 1212 cm⁻¹ ;

NMR (CDCl₃): δ3.29-3.41 (2H, m, CH₂ indole); 3.71 (3H, S, CO₂ CH₃);5.00-5.05 (1H, m, CH₂ CH); 6.13 (1H, b, NHCHO); 6.98 (1H, s, indole-H₂);7.09-7.21 (2H, m, indole-H₅ H₆); 7.35 (1H, d, J=8.0 Hz indole-H₇); 7.53(1H, d, J=7.8 Hz, indole-H₄); 8.14 (1H, s, NHCHO); 8.20 (1H, b,indole-NH).

Step 2

N-Formyl-RS-tryptophamnethylester (1.50 g, 6.09 mmol) was stirred anddissolved in anhydrous DMF (20 mL) and cooled in an ice bath.4-Dimethylaminopyridine (0.075g, 0.61 mmol) was added followed bydropwise addition of ditertbutyldicarbonate (1.33 g, 6.09 mmol) inanhydrous DMF (20 mL) added over 1 hour. The cold solution was stirredfor 18 hours with slow rewarming to room temperature. The mixture waspoured into water (300 mL) and extracted with Et₂ O (3×100 mL). Thecombined Et₂ O extracts were washed with water (3×100 mL), dried overMgSO₄, filtered and the solvent removed in vacuo. The residue waspurified by chromatography on silica using 50% n-hexane/50% EtOAc aseluant giving the product as a white solid (1.71 g, 81%); mp 61°-62° C.;

IR (film): 3306, 2979, 1733, 1688, 1454, 1371, and 1158 cm⁻¹ ;

NMR (CDCl₃): δ1.66 (9H, s, ##STR110## 3.20-3.34 (2H, m, CH₂ indole);3.71 (3H, S, CO₂ CH₃); 4.98-5.04 (1H, m, CH₂ CHCO₂ CH₃); 6.32 (1H, d,J=7.4 Hz, NHCHO); 7.20-7.33 (2H, m, indole-H₅ H₆); 7.39 (1H, s,indole-H₂); 7.48 (1H, d, J=7.9 Hz, indole-H₄); 8.09 (1H, d, J=8.1 Hz,indole-H₇); 8.18 (1H, s, NHCHO).

Step 3

BOC-N-formyl-RS-tryptophanmethylester (3.25 g, 9.38 mmol) was stirredand dissolved in CH₂ Cl₂ (75 mL) and cooled in an ice bath. Et₃ N (7.84mL, 56.28 mmol) was added followed by a solution of triphosgene (1.02 g,3.44 mmol) in CH₂ Cl₂ (25 mL) added dropwise over 45 minutes. The coldsolution was stirred for 3 hours with slow rewarming to roomtemperature. The CH₂ Cl₂ solution was then washed with 5% citric acidsolution (3×25 mL), saturated NaHCO₃ solution (25 mL) and brine (25 mL),dried over MgSO₄, filtered, and the solvent removed in vacuo. Theresidue was purified by chromatography on silica using 67% n-hexane/33%EtOAc as eluant giving the product as an off-white solid (2.26 g, 73%);mp 90°-91° C.;

IR (film): 2980, 2149, 1760, 1733, 1454, 1372, 1157, and 1088 cm⁻¹ ;

NMR (CDCl₃): δ1.67 (9H, s, ##STR111## 3.28 (1H, dd, J=14.7 and 8.0 Hz,CHH indole); 3.41 (1H, dd, J=14.7 and 4.9 Hz, CHH indole); 3.79 (3H, s,CO₂ CH₃); 4.54-4.58 (1H, m, CH₂ CHCO₂ CH₃); 7.23-7.36 (2H, m, indole-H₅H₆); 7.50 (1H, d, J=7.8 Hz, indole-H₄); 7.59 (1H, s, indole-H₂); 8.16(1H, d, J=8.2 Hz, indole-H₇).

Step 4

1,3-Dimethyl-3,4,5-tetrahydro-2(1H)-pyrinidinone (DMPU) (0.121 mL, 1.0mmol) was added to a stirred solution of the isonitrile (0.328 g, 1.0mmol) in anhydrous THF (10 mL) at -78° C. To this was addedlithiumhexamethyldisilazide (1.1 mL, 1.0 mmol, 1.1 mmol) and the mixturestirred for 30 minutes. Bromoacetonitrile (0.077 mL, 1.1 mmol) was addedand the mixture stirred for 1 hour at -78° C. and then at roomtemperature for 1.5 hours. The mixture was poured into water (25 mL) andextracted with Et₂ O (2×25 ml), the combined extracts washed once withbrine (25 mL), the Et₂ O dried over MgSO₄, filtered, and the solventremoved in vacuo. The residue was purified by chromatography on silicausing 75% n-hexane/25% EtOAc as eluant giving the product as a whitesolid (0.315 g, 86%); mp 92°-93° C.; IR (film): 2981, 1737, 1454, 1371,1259, and 1156 cm⁻¹ ;

NMR (CDCl₃): δ1.68 (9H, s, CO₂ C(CH₃)₃); 2.98 (1H, d, J=16.7 Hz, indoleCHH); 3.09 (1H, d, J 16.8 Hz indole CHH); 3.47 (2H, d, J=3.7 Hz, CH₂CN); 3.76 (3H, s, CO₂ CH₃); 7.24-7.37 (2H, m, indole-H₅ H₆); 7.51 (1H,d, J=7.6 Hz, indole-H₄); 7.62 (1H, s, indole-H₂); 8.15 (1H, d, J=8.1 Hz,indole-H₇);

Analysis calculated for C₂₀ H₂₁ N₃ O₄ : C, 65.38; H, 5.76; N, 11.44%.Found: C, 65.23; H, 5.90; N, 11.36%.

Step 5

4.7M HCl in 1,4-dioxan (1.0 mL, 4.7 mmol) was added to a stirredsolution of the isonitrile (0.413 g, 1.12 mmol) in EtOAc (10 mL) cooledto 5° C. To this mixture was added water (1.0 mL) and the solutionstirred at room temperature for 1 hour. The solvents were removed invacuo and the residual solid partitioned between saturated NaHCO₃solution (10 mL) and EtOAc (2×25 mL). The combined EtOAc extracts werewashed once with brine (25 mL), dried over MgSO₄, filtered, and thesolvent removed in vacuo. The residue was purified by chromatography onsilica using 50% n-hexane/50% EtOAc as eluant giving the product as asyrup (0.301 g, 75%). IR (film): 3380, 2979, 2256, 1734, 1454, 1370,1258, 1157 cm⁻¹ ;

NMR (CDCl₃): δ1.67 (9H, s, ##STR112## 1.88 (2H, bs, NH₂); 2.74 (1H, d,J=16.5 Hz, CHHCN); 2.89 (1H, d, J=16.4 Hz, CHHCN); 3.12 (1H, d, J=14.3Hz, indole CHH); 3.25 (1H, d, J=14.2 Hz, indole CHH); 3.69 (3H, s, CO₂CH₃); 7.22-7.35 (2H, m, indole-H₅ H₆); 7.46 (1H, s, indole-H₂); 7.52(1H, d, J=7.6 Hz, indole-H₄); 8.13 (1H, d, J 8.1 Hz, indole-H₇);

Analysis calculated for C₁₉ H₂₃ N₃ O₄ O.3H₂ O: C, 63.85; H, 6.49; N,11.76%. Found: C, 63.82; H, 6.64; N, 11.49%.

Step 6

The amine (0.561 g, 1.57 mmol) was stirred and dissolved in 1,4-dioxan(10 mL) and water (0.5 mL) added. Na₂ CO₃ (0.832 g, 7.85 mmol) was addedfollowed by benzylchloroformate (0.448 mL, 3.14 mmol) and the reactionstirred at room temperature for 1 hour. The 1,4-dioxan was removed invacuo and the residue partitioned between EtOAc (50 mL) and brine (2×25mL). The EtOAc solution was dried over MgSO₄. filtered, and the solventremoved in vacuo. The residue was purified by chromatography on silicausing 67% n-hexane/33% EtOAc as eluant to give the product as a syrup(0.662 g, 86%);

IR (film): 3342, 2929, 2253, 1732, 1454, 1372, 1156, 1089 cm⁻¹ ;

NMR (CDCl₃): δ1.66 (9H, s, ##STR113## 3.24-3.34 (2H, m, CH₂ CN);3.47-3.62 (2H, m, CH₂ indole); 3.67 (3H, s, CO₂ CH₃); 5.14 (2H, s, PHCH₂OCO); 5.78 (1H, s, NHCOO); 7.15-7.20 (1H, m, indole); 7.28-7.43 (12H, m,Ar); 8.10 (1H, d, J=8.4 Hz, indole-H₇);

Analysis calculated for C₂₇ H₂₉ N₃ O₆ : C, 65.97; H, 5.95; N, 8.55%.Found: C, 65.72; H, 6.01; N, 8.29%

Step 7

The BOC protected ester (0.119 g, 0.24 mmol) was stirred and dissolvedin CH₂ Cl₂ (2 mL) at room temperature. Trifluoroacetic acid (1.0 mL) wasadded and the mixture stirred at room temperature for 2 hours. Thesolvents were removed in vacuo to give the product as a syrup whichformed a foam out of Et₂ O (0.078 g, 87%);

IR (film): 3358, 2254, 1718, 1457 cm⁻¹ ;

NMR (CDCl₃): δ3.27 (1H, d, J=6.2 Hz, CHHCN); 3.32 (1H, d, J=8.8 Hz,CHHCN); 3.53-3.63 (2H, m, CH₂ indole); 3.70 (3H, s, CO₂ CH₃); 5.11 (1H,d, J=12.1 Hz, OCHHPh); 5.21 (1H, d, J=12.1 Hz, OCHHPh); 5.87 (1H, s,NHCOO); 7.22-7.45 (10H, m, indole, C₆ H₅); 8.17 (1H, d, J=8.2 Hz,indole-NH);

Step 8

LiOH-H₂ O (0.040 g, 0.95 mmol) was added to a stirred solution of themethylester (0.070 g, 0.19 mmol) in THF:H₂ O (4 mL, 3:1 mixture) at roomtemperature. The mixture was stirred at room temperature for 16 hoursand the THF removed in vacuo. The residue was diluted with water (10 mL)and extracted once with Et₂ O (10 mL). The aqueous solution was made pH4 with 5% citric acid solution and the product extracted into EtOAc(3×10 mL). The combined EtOAc extracts were dried over MgSO₄, filtered,and the solvent removed in vacuo giving the product as a foam (0.045 g,65%);

IR (film): 3401, 2586, 1712 cm⁻¹ ;

NMR (CDCl₃): δ3.25-3.37 (3H, m, CH₂ CN, CHH indole); 3.54-3.59 (1H, m,CHH indole); 5.05 (1H, d, J=12.3 Hz, OCHHPh); 5.14 (1H, d, J=12.1 Hz,OCHHPh); 5.76 (1H, b, NHCOO); 6.89 (1H, s, indole-H₂); 7.02-7.16 (2H, m,indole-H₅ H₆); 7.28-7.31 (6H, m, indole, C₆ H₅); 7.58 (1H, d, J=7.7 Hz,indole); 8.24 (1H, s, indole-NH);

Step 9

N,N'-dicyclohexylcarbodiimide (0.028 g, 0.138 mmol) was added to astirred solution of the acid (0.045 g, 0.125 mmol) and1-hydroxybenzotriazole monohydrate (0.023 g, 0.150 mmol) in EtOAc (2mL). The mixture was stirred for 2 hours at room temperature and theN,N'-dicyclohexylurea filtered off. A solution of(S)-(-)-α-methylbenzylamine (0.023 g, 0.188 mmol) in EtOAc (0.5 mL) wasadded and the mixture stirred at room temperature for 21 hours. Themixture was filtered and diluted with EtOAc (25 mL) and the EtOAcsolution washed with 5% citric acid solution (2×10 mL), once withsaturated NaHCO₃ solution (10 mL), and once with brine (10 mL). TheEtOAc solution was dried over MgSO₄. filtered, and solvent removed invacuo. The residue was purified by chromatography on silica using 67%n-hexane/33% EtOAc as eluant giving the product as a white amorphoussolid (0.023 g, 40%);

IR (film): 3337, 3033, 2931, 2251, 1717, 1656, 1496, 1257 cm⁻¹ ;

NMR (CDCl₃): δ0.98 (1.5H, d, J 6.7 Hz, 0.5 CH₃); 1.29 (1.5H, d, J=7.4Hz, 0.5 CH₃); 3.16-3.57 (4H, m, indole CH₂, CH₂ CN); 4.82-4.95 (1H, m,PhCHNHCO); 5.01-5.19 (2H, m, CH₂ Ph); 5.55 (1H, d, J=8.9 Hz, NHCOO);6.03 (0.5H, d, J=7.3 Hz, 0.5 CONH); 6.12 (0.5H, d, J=7.7 Hz, 0.5 CONH);6.56 (0.5H, s, 0.5 indole-H₂); 6.97-7.37 (13.5H, m, Ar); 7.54-7.61 (1H,m, Ar); 7.98 and 8.29 (1H, two s, indole-NH).

Analysis calculated for C₂₉ H₂₈ N₄ O₃ : C, 72.48; H, 5.87; N, 11.66%.Found: C, 72.29; H, 5.97; N, 11.48%.

EXAMPLE 63

Carbamic acid, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!-, 2-benzofuranylmethyl ester, R-(R*,S*)!##STR114## Step 1

To a stirred solution of 2-benzofuranylmethanol (Garter R, J Am Chem Soc1951;73:4400) (1.48 g, 10 mmol) and 4-nitrophenylchloroformate (2.01 g,10 mmol) in CH₂ Cl₂ (50 mL, a) at 0° C. was added dropwise a solution ofpyridine (0.79 g, 10 mmol) in CH₂ Cl₂ (10 mL). The reaction mixture wasallowed to warm to room temperature overnight. The solvent removed underreduced pressure and the residue taken up between EtOAc (50 mL) and 10%citric acid solution (50 mL). The organic phase was washed successivelywith 10% citric acid solution (2×50 mL), H₂ O (50 mL), saturated NaHCO₃solution (5×50 mL), brine (50 mL), dried (MgSO₄), filtered, and solventremoved under reduced pressure. The product was then recrystallized fromEt₂ O to give pure carbonate (1.80 g, 58%); mp 90.5°-92.5° C.;

¹ H NMR (CDCl₃): δ5.41 (2H, s, CH₂ O); 6.90 (1H, s, benzofuran C3-H);7.21-7.42 (2H, m, ArH); 7.39 (2H, d, 9.2 Hz, ArH's meta to NO₂); 7.52(1H, d, 7.8 Hz, ArH); 7.60 (1H, d, 7.1 Hz, ArH); 8.28 (2H, d, 9.2 Hz,ArH's ortho to NO₂);

IR (film): 3119, 1770, 1617, 1594, 1524 cm⁻¹ ;

MS m/e (CI) 313;

Analysis calculated for C₁₆ H₁₁ NO₆ (C,H,N).

Step 2

To a stirred solution of the carbonate (185 mg, 0.6 mmol) andα-methyltryptophanyl-1-phenethylamide (160 g, 0.5 mmol) in DMF (5 mL)was added 4-dimethylaminopyridine (61 mg, 0.5 mmol) and the mixture leftto stir overnight at room temperature. The solvent was removed at 60° C.under reduced pressure, the residue taken up in EtOAc (100 mL) andwashed successively with 10% citric acid solution (3×30 mL), H₂ O (30mL), 1N NaOH (5×30 mL), brine (2×50 mL), dried (MgSO₄), filtered, andthe solvent removed under reduced pressure. The residue was thenpurified by chromatography on reverse phase silica eluting with 35% H₂ Oin MeOH. Crystallization from Et₂ O gave pure product (140 mg, 56%); mp103°-111° C.;

¹ H NMR (CDCl₃): δ1.31 (3H, d, 6.9 Hz, CHCH₃); 1.63 (3H, s, CCH₃); 3.25(1H, d, 14.8 Hz, CHH-indole); 3.47 (1H, d, 14.8 Hz, CHH-indole);4.95-5.05 (1H, m, NHCHCH₃); 5.14 and 5.21 (each 1H, each d, 13.2 Hz,CHHO); 5.41 (1H, s, OCONH); 6.30-6.35 (1H, bd, CONHCH); 6.74 (1H, s,benzofuran C3-H); 6.78 (1H, d, 2.3 Hz, indole C2-H); 7.05-7.33 (10H, m,ArH); 7.45 (1H, d, 8.4 Hz); 7.52-7.58 (2H, m, ArH); 7.85 (1H, s, indoleNH);

α!_(D) =+17.6° C. (c=0.5, 21° C., MeOH);

IR (film): 3334, 1715, 1651 cm⁻¹ ;

MS m/e (FAB) 496.3 (M⁺ +H);

Analysis calculated for C₃₀ H₂₉ N₃ O₄ (C,H,N).

EXAMPLE 64

Carbamic acid, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-(1-phenylethyl)amino!ethyl!-, benzo b!thien-2-yl-methyl ester,R-(R*,S*)! ##STR115## Step 1

Method as for Example 63 using benzo b!thiophene-2-methanol (Blicke F F,Sheets D G. J Am Chem Soc. 1949;71:2856) (1.64 g, 10 mmol). On removalof ethylacetate under reduced pressure, a crystalline solid formed. Thiswas washed with ether to give carbonate (1.78 g, 54%); mp 119°-121.5°C.;

¹ H NMR (CDCl₃): δ5.54 (2H, s, CH₂ O); 7.34-7.45 (3H, m, ArH); 7.39 (2H,d, 9.1 Hz, ArH's meta to NO₂); 7.74-7.90 (2H, m, ArH); 8.28 (2H, d, 9.2Hz, ArH's ortho to NO₂);

IR (film): 3083, 1763, 1616, 1593, 1523, 1349, 1214, 860 cm⁻¹ ;

MS m/e (CI) 329;

Analysis calculated for C₁₆ H₁₁ NO₅ S (C,H,N,S).

Step 2

Method as for Example 63 using 198 mg (0.6 mmol) of carbonate. The crudeproduct was purified using normal phase silica eluting with 40% EtOAc inhexane. Crystallization from Et₂ O gave pure product (236 mg, 92%); mp146°-150° C.;

¹ H NMR (CDCl₃) : δ1.28 (3H, d, 6.9 Hz, CHCH₃); 1.64 (3H, s, CCH₃) ;3.25 (1H, d, 14.8 Hz, CHH-indole); 3.47 (1H, d, 14.8 Hz, CHH-indole);4.95-5.05 (1H, m, NHCHCH₃); 5.27 (1H, d, 13.0 Hz, CHHO); 5.34 (1H, d,13.1 Hz, CHHO); 5.42 (1H, s, OCONH); 6.28-6.35 (1H, bd, CONHCH); 6.78(1H, s, indole C₂ -H); 7.05-7.35 (11H, m, ArH); 7.58 (1H, d, 7.9 Hz,indole C₄ -H); 7.70-7.80 (2H, m, ArH); 7.89 (1H, s, indole NH);

α!_(D) =+18° C. (c=0.5, 19° C., MeOH);

IR (film): 3344, 1714, 1651, 1494, 1456, 1249, 1128, 1067, 744 cm⁻¹ ;

MS m/e (FAB) 512.2 (M⁺ +H);

Analysis calculated for C₃₀ H₂₉ N₃ O₃ S (C,H,N,S).

EXAMPLE 65

2-(1H-Indol-3-yl)-1-methyl-1-(1-phenyl-ethyl-carbamoyl)-ethyl!-carbamicacid 2-fluoro-5-methylbenzyl ester ##STR116## Step 1

A solution of 2-fluoro-5-methylbenzoic acid (2 g, 13 mmol) in THF (30mL) was added slowly to a stirred suspension of NaBH₄ (593 mg, 15.6mmol) in THF (30 mL) at room temperature under nitrogen. The mixture wasstirred until effervescence ceased, before iodine was added slowly (1.65g, 6.5 mmol) to the reaction mixture. The reaction mixture was stirredfor a further 72 hours during which time an extra equivalent each ofNaBH₄ and iodine were added to cause the reaction to go to completion.2M HCl (5 mL) was carefully added to the reaction mixture undernitrogen. Ether was then added and the organic phase was separated fromthe aqueous phase. This was washed with NaHCO₃ (aq), water, dried(MgSO₄) and concentrated in vacuo. The residue was purified by silicagel flash chromatography, eluting with a gradient of hexane tohexane:EtoAc (9:1) to provide the alcohol as a clear oil (1.42 g, 78%yield);

¹ H NMR (CDCl₃): δ2.28 (3H, s, CH₃); 2.37 (1H, Bs, OH); 4.65 (2H, d,J=4.8 Hz, CH₂ OH); 6.86-6.91 (1H, m, ArH); 6.99-7.03 (1H, m, ArH);7.15-7.17 (1H, m, ArH);

IR (film): 3346, 2926 (sm), 2886 (sm), 1501, 1457 (sm), 1247, 1228,1205, 1140, 1121, 1042, 1020, 814 cm⁻¹ ;

MS m/e (CI) M=140;

Step 2

The alcohol was converted to the carbonate via the method used forExample 63;

¹ H NMR (CDCl₃): δ2.32 (3H, s, CH₃); 5.31 (2H, s, CH₂ O); 6.96-7.0 (1H,m, ArH of F-Ph); 7.13-7.16 (1H, m, ArH of F-Ph); 7.21-7.23 (1H, m, ArHof F-Ph); 7.35-7.39 (2H, m, 2ArH of P-NO₂ Ph); 8.22-8.27 (2H, m, 2ArH ofp-NO₂ Ph);

IR (film): 1767, 1617 (sm), 1594 (sm), 1525, 1504, 1348, 1210, 1164, 862cm⁻¹ ;

MS m/e (CI) 306=M+H⁺.

Step 3

The carbonate (366 mg, 1.2 mmol), the α-methyltryptophonyl-1-phenethylamide (385 mg, 1.2 mmol) anddimethylaminopyridine (147 mg, 1.2 mmol) were stirred in DMF (100 mL) atroom temperature overnight. The reaction mixture was taken up in EtoAcand washed with NaHCO₃ (aq), Na₂ CO₃ (aq), 1N HCl, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with 7:3 hexane:EtoAc to give 9 (iii) as a whitesolid (0.195 g, 77%); mp 104°-106° C.;

¹ H NMR (CDCl₃): 1.28 (3H, d, J=7.2 Hz, NHCHCH₃); 1.60 (3H, s, αMe);2.26 (3H, s, Ph-CH₃); 3.24 (1H, d, J=14.8 Hz, CHH indole); 3.45 (1H, d,J=14.8 Hz, CHHindole); 4.95-5.03 (1H, m, NHCHCH₃ ; 5.06 and 5.12 (2H,2×d, J=12.5 and 12.0 Hz, CH₂ OCONH 5.3-5.4 (1H, m, OCONH); 6.34 (1H, bd,J=7.8 Hz, CONHCH); 6.79-7.32 (12H, m, 12 ArH); 7.56 (1H, d, J=8.1 Hz,ArH); 7.90-7.95 (1H, Bs, NHindole);

α!_(D) ²³.2° C. =+7.74° C. (C=0.155 g 100 mL⁻¹, MeOH);

IR (film): 3334, 2927, 1715, 1652, 1505, 1456, 1251, 1072, 743 cm⁻¹ ;

MS m/e (FAB): 488.3=M+H⁺ ;

Analysis calculated for C₂₉ H₃₀ FN₃ O₃ (C,H,N).

EXAMPLE 66

Carbamic acid, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-1-(4-pyridinyl)ethyl!amino!ethyl!-, 2-benzofuranylmethyl ester,monohydrochloride, R-(R*,S*)! ##STR117## Step 1

To a suspension of lithium aluminum hydride (2.82 g, 63 mmol) in dry THF(150 mL) at -5° C. under nitrogen was added dropwise a solution ofbenzofuran-2-carboxylic acid (10.2 g, 63 mmol) in THF (100 mL). Thereaction mixture was allowed to warm to room temperature and stirred for16 hours. 1N HCl was added slowly with cooling (cardice-acetone bath)and the resulting solution was washed with 1N HCl, NaHCO₃(aq), dried(MgSO₄) and the solvent removed in vacuo. The residue was purified byflash chromatography on silica eluting with a mixture of hexane:EtOAc(1:1) to give the alcohol as a yellow oil (7.2 g, 77%);

¹ H NMR (CDCl₃): δ2.68 (1H, s, OH); 4.70 (2H, s, CHHOH); 6.58 (1H, s,ArH3); 7.15-7.27 (2H, m, ArH); 7.42 (1H, d, 8.1 Hz, ArH); 7.48-7.51 (1H,m, ArH);

Analysis calculated for C₉ H₈ O₂ (C,H,N).

Step 2

To a stirred solution of the alcohol from Step 1 (8.58 g, 58 mmol) andpyridine (4.82 mL, 58 mmol) in CH₂ Cl₂ (150 mL) at 10° C. was addeddropwise a solution of p-nitrophenyl chloroformate (14 g, 70 mmol) inCH₂ Cl₂ (150 mL). The reaction mixture was allowed to warm to roomtemperature and stirred for 18 hours. The solvent was removed in vacuoand the residue taken up in EtOAc, washed with 1N HCl, NaHCO₃(aq), dried(MgSO₄) and concentrated in vacuo. The resultant yellow solid waspurified using hexane:ether (9:1) as eluant to give the carbonate as acream solid (9.8 g, 54%);

IR (film): 3119, 1770, 1617, 1594, 1524, 1346, 1251, 1213, 862, 753 cm⁻¹; mp 90.5°-92.5° C.;

¹ H NMR (CDCl₃): δ5.41 (2H, s, CHHO); 6.90 (1H, s, H2 of benzofuran);7.21-7.42 (2H, m, ArH); 7.39 (2H, d, 9.2 Hz, H2, H6 of phenyl); 7.52(1H, d, 7.8 Hz, ArH); 7.60 (1H, d, 7.1 Hz, ArH); 8.28 (2H, d, 9.2 Hz,H3, H5, of phenyl);

Analysis calculated for C₁₆ H₁₁ NO₆ (C,H,N).

Step 3

The mixed carbonate from Step 2 (7 g, 22 mmol), (R)α-methyltryptophan,methyl ester (5.2 g, 22 mmol), and dimethylaminopyridine (2.7 g, 22mmol) were stirred in DMF (60 mL) at room temperature overnight. Thereaction mixture was taken up in ether, washed with NaCO₃(aq), 1N HCl,dried (MgSO₄) and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with hexane:EtOAc (7:3) togive the urethane as a yellow sticky solid (8.57 g, 96%);

¹ H NMR (CDCl₃): δ1.70 (3H, s, αCH₃); 3.36 (1H, d, 14.6 Hz, CHH indole);3.54 (1H, bd, 13.9 Hz, CHH indole); 3.67 (3H, s, CO₂ CH₃); 5.17 (l, d,13.4 Hz, CHHOCONH); 5.27 (1H, d, 13.2 Hz, CHHOCONH); 5.58 (1H, bs,OCONH); 6.78 (1H, s, ArH); 6.81 (1H, s, ArH); 7.00 (1H, t, 7.6 Hz, ArH);7.12 (1H, t, 7.3 Hz, ArH); 7.23-7.34 (3H, m, ArH); 7.47-7.50 (2H, m,ArH); 7.81 (1H, bs, indole NH).

Step 4

To a solution of the urethane (8.57 g, 21 mmol) in THF (90 mL) was addedlithium hydroxide (30 mL, 10 M), methanol (30 mL) and water (60 mL) andthe reaction was stirred at room temperature for 2 days. The volatileswere removed in vacuo and the aqueous mixture was acidified with 1N HCl,and extracted with EtOAc. The organic phase was washed with water, dried(MgSO₄) and concentrated in vacuo to yield the acid as a yellow oil(8.23 g, 100%) which was used without further purification in the nextstep.

Step 5

To a solution of the acid (8.23 g, 21 mmol) in EtOAc was addeddicyclohexylcarbodiimide (4.3 g, 21 mmol) followed by pentafluorophenol(3.86 g, 21 mmol) and the mixture was stirred at room temperature for 16hours. The mixture was cooled to 0° C. for 30 minutes and the resultingprecipitate of dicyclo hexylurea was removed by filtration. The filtratewas washed with 1N HCl, NaCO₃(aq), dried (MgSO₄) and the solventsremoved in vacuo. The residue was purified by flash chromatography onsilica gel eluting with a mixture of hexane:EtOAc (9:1) to give thepentafluorophenyl ester as a cream solid (7.5 g, 64%).

IR (film): 3418, 1785, 1707, 1652, 1520, 1455, 1254 cm⁻¹ ;

MS m/e (CI): 559 (M+H);

¹ H NMR (CDCl₃): δ1.74 (3H, s, αCH₃); 3.44 (1H, d, 14.9 Hz, CHH indole);3.66 (1H, d, 14.6 Hz, CHH indole); 5.18-5.29 (3H, m, CHHOCONH); 6.79(1H, s, ArH); 7.0 (1H, s, ArH); 7.04 (1H, t, 7.6 Hz, ArH); 7.18 (1H, t,7.5 Hz, ArH); 7.21-7.36 (3H, m, ArH); 7.46 (1H, d, 8.1 Hz, ArH);7.55-7.58 (2H, m, ArH); 8.02 (1H, bs, indole NH);

Analysis calculated for C₂₈ H₁₉ F₅ N₂ O₅ (C,H,N).

Step 6

Hydroxyl amine sulfate (11.13 g, 68 mmol) and potassium hydroxide (7.58g, 135 mmol) as aqueous solutions, were added in quick succession to amethanolic solution (100 mL) of 4-acetylpyridine (2.73 g, 23 mmol) andthe mixture was stirred overnight. The solvent was removed and theresidue was taken up in EtOAc and washed with water, dried (MgSO₄) andconcentrated in vacuo. The resulting solid was washed with ether anddried to yield the oxime as a solid (2.25 g, 72%).

Step 7

To a solution of the oxime (2.079 g, 15.3 mmol) in methanol (50 mL) wasadded Pearlman's catalyst in methanol (2 micro spatulas in 5 ml). Thereaction mixture was shaken under a hydrogen pressure of 46 psi and at30° C. in a Parr Apparatus for 18 hours. The reaction mixture wasfiltered through Keiselguhr and the filtrate concentrated in vacuo toyield a racemic mixture of the free amine. The amine was taken up inmethanol (5 mL) and one equivalent of (S)-tartaric acid (2.3 g, 15.3mmol) in H₂ O (3 mL) was added. The tartrate salt was filtered off andrecrystallized in aqueous methanol twice to yield the (S) (S) tartratesalt of the amine homochirally pure α!_(D) ²².8° C. =+14.88 (H₂ O,C=0.625 g 100 mL⁻¹). The tartrate salt of the amine ( s! s!) was takenup in water, basified to pH 14 and re-extracted with EtOAc. The organiclayer was dried and concentrated in vacuo to yield the free amine;

α!_(D) ²⁰.6 =-23.12 (ELOH). (J Am Chem Soc 95:7525 (1973))

Step 8

The pentafluorophenyl ester from Step 5 (335 mg, 0.6 mmol) and the aminefrom step 7 (7.3 mg, 0.6 mmol) were stirred at room temperature in DMF(80 mL) for 24 hours. The reaction mixture was washed with NaHCO₃(aq),brine, dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby silica gel flash chromatography, eluting with a gradient ofhexane:EtoAc (6:4) to hexane;EtOAc (2:8). The amide was obtained as awhite solid (165 mg, 55%); mp 198.5°-199.5° C.;

α!_(D) ²¹.1° C. =+34.62 (c=0.065 g 100 mL⁻¹, MeOH);

IR (film): 3395, 3322, 1715, 1645, 1521, 1455, 1253, 1070 cm⁻¹ ;

MS m/e (FAB): 497.3=M+H⁺ ;

¹ H NMR (CDCl₃): δ1.28 (3H, d, J=6.8 Hz, CHCH₃); 1.62 (3H, s obscured bywater peak!, αCH₃); 3.22 (1H, d, J=14.9 Hz, CHH indole); 3.53 (1H, d,J=14.0 Hz, CHH indole); 4.91-5.00 (1H m, NHCH Pyr); 5.17 (1H, d, J=13.4Hz, CHHOCONH); 5.25 (1H, d, J=13.2 Hz, CHHOCONH); 5.33 (1H, s, OCONH);6.49 (1H, bd, NHCHCH₃); 6.79 (2H, d, J=12 Hz, 2ArH), 7.06-7.36 (7H, m,7ArH); 7.46 (1H, d, J=8.4 Hz, 1ArH); 7.56 (2H, d, J=8 Hz, 2ArH); 7.97(1H, s, indole NH); 8.47 (2H, d, J=4.4 Hz, 2Ar pyridyl protons);

Analysis calculated for C₂₉ H₂₈ N₄ O₄ (C,H,N).

Step 9

To a solution of the pyridine derivative from Step 8 in EtOAc was addedover one equivalent of HCl in dioxan (2 mL, 4M) causing thehydrochloride salt to precipitate out. The salt was filtered and washedthoroughly with ether before repeated triturations with EtOAc/ethermixtures yielded the hydrochlorine salt as a white solid (0.134 g, 45%);mp 125°-128° C.;

α!_(D) ²³.0° C =+57.5° C. (c=0.08 g 100 mL⁻¹, MeOH);

IR (film): 3270, 3060, 1710, 1660, 1614, 1505, 1455, 1362, 1251, 1070cm⁻¹ ;

MS m/e (FAB): 497.4=M+H⁺ -Cl;

¹ H NMR (DMSO): δ1.31 (3H, s, CHCH₃); 1.33 (3H, s, αCH₃); 3.13 (1H, d,J=14.4 Hz, CHH indole); 3.33-3.38 (1H, m, CHH indole); 4.98-5.07 (1H, m,NHCHCH₃); 5.19 (2H, 2xd, no J value available, CH₂ OCONH); 6.82 (1H,t^(t), J=7.6 and 7.2 Hz, ArH); 6.95-6.97 (2H, m, 2ArH); 7.2-7.38 (4H, m,4ArH); 7.40 (1H, d, J=8 Hz, ArH); 7.52 (1H, d, J=8.4 Hz, ArH); 7.61 (1H,d, J=8 Hz, ArH); 7.91 (1H, d, J=5.2 Hz, ArH); 8.36 (1H, d, J=6.8 Hz,CONHCH); 8.78 (2H, d, J=5.6 Hz, H² and H⁶ of pyridine); 10.89 (1H, s,indole NH);

Analysis calculated for C₂₉ H₂₉ ClN₄ O₄.0.85 H₂ O (C,H,N).

EXAMPLE 67

Carbamic acid, 1-(1H-indol-3-ylmethyl)-2-methyl-(phenylmethyl)amino!-2-oxoethyl!-, 2-benzofuranylmethyl ester,(S) ##STR118## Step 1

To a stirred solution of Boc-(S)-tryptophan-O-succinimidyl ester (5.1 g,12.6 mmol) in ethyl acetate (150 mL) at room temperature was addedN-methylbenzylamine (1.68 g, 13.9 mmol) in ethyl acetate (50 mL)dropwise. The mixture was stirred at room temperature for 120 hours andthen washed with 1N HCl (aq), NaHCO₃ (aq), brine, dried (MgSO₄), andconcentrated in vacuo. The residue was chromatographed on silica gelusing a gradient of 10% ether in dichloromethane to 50% ether indichloromethane to elute the pure compound. Concentration in vacuo gavethe product as a white foam (5.13 g, 95%); mp 56°-58° C.;

IR (film): 3303, 1699, 1635 cm⁻¹ ;

¹ H NMR (CDCl₃): δ1.41 (3H, s, t-Bu); 1.44 (6H, s, t-Bu); 2.55 (2H, s,N-Me); 2.75 (1H, s, N-Me); 3.19 (2H, d, 7 Hz, βCH₂); 3.96 (0.3H, d, 16Hz, CH₂ Ph); 4.34 (0.3H, d, 16 Hz, CH₂ Ph), 4.43 (1.4H, s, CH₂ Ph); 5.00(1H, m, α-H); 5.47 (1H, m, OCONH); 6.90-7.35 (9H, m, aromatics); 7.54(0.33H, d, 7.5 Hz, aromatics); 7.68 (0.66H, d, 7.5 Hz, aromatics); 7.98(0.66H, s, indole NH); 8.04 (0.33H, s, indole NH);

Analysis calculated for C₂₄ H₂₉ N₃ O₃.0.25 EtoAc (C,H,N).

Step 2

Boc-(S)-tryptophan-N-methylbenzylamide (5.00 g, 12.3 mmol) was dissolvedin a mixture of trifluoroacetic acid:water (9:1) (50 ml) and stirred for45 minutes at room temperature. The solvent was removed in vacuo, theresidue taken up in ethyl acetate (100 mL), washed with NaHCO₃ (aq),brine, dried (MgSO₄) and concentrated in vacuo. The residue waschromatographed on silica gel, eluting with methanol:dichloromethane(10-20%, 60 minutes) to give the product as a white solid (2.60 g, 69%);

mp 118°-122° C.;

IR (film): 3290, 1633 cm⁻¹ ;

¹ H NMR, (CDCl₃): δ2.74 (2H, s, N-Me); 2.92 (1H, s, N-Me); 2.98 (1H, m,β-CH₂); 3.17 (1H, m, β-CH₂); 3.98 (0.33H, t, 7 Hz, α-H); 4.11 (0.66H, t,7 Hz, α-H); 4.20 (0.5H, d, 17 Hz, CH₂ Ph) ; 4.44 (0.5H, d, 17 Hz, CH₂Ph); 4.49 (0.5H, d, 14.5 Hz, CH₂ Ph); 4.60 (0.5H, d), 14.5 Hz, CH₂ Ph);7.01-7.37 (10.3H, m, aromatics); 7.59 (0.66H, d, 8 Hz, aromatics); 8.20(1H, s, indole NH);

Analysis calculated for C₁₉ H₂₁ N₃ O.0.3H₂ O (C,H,N) .

Step 3

To a stirred solution of 2-benzofuranyl p-nitrophenyl carbonate (157 mg,0.5 mmol) in DMF (3 ml) was added (S)-tryptophan-N-methylbenzylamide(154 mg, 0.5 mmol) in DMF (2 mL) and stirring continued overnight atroom temperature. The solvent was removed in vacuo and the residue takenup in ethyl acetate, washed with 1N HCl (aq), NaHCO₃ (aq), brine, dried(MgSO₄) and concentrated in vacuo. The residue was chromatographed onreverse phase silica (C18) using a gradient of 70% to 90% acetonitrilein water (0.1% TFA) to elute the pure compound (93 mg, 39%); mp 63°-65°C.;

IR (film): 3296, 1714, 1634 cm⁻¹ ;

MS m/e (FAB): 482.6=M+H;

¹ H NMR (CDCl₃): δ2.48 (2H, m, N-Me); 2.80 (1H, m, N-Me); 3.20 (2H, m,β-CH₂); 3.98 (0.5H, d, 16.5 Hz, CH₂ Ph); 4.37 (0.5H, d, 16.5 Hz, CH₂Ph); 4.40 (0.5H, d, 15 Hz, CH₂ Ph); 4.47 (0.5H, d, 15 Hz, CH₂ Ph); 5.11(1H, m, α-H); 5.22 (2H, m, ArCH₂ O); 5.78 (1H, m, OCONH); 6.70-7.69(15H, m, aromatics); 7.87 (0.5H, s, indole NH); 7.95 (0.5H, s, indoleNH);

Analysis calculated for C₂₉ H₂₇ N₃ O₄ (C,H,N).

EXAMPLE 68

Carbamic acid, 1-(1H-indol-3-ylmethyl)-2-methyl(phenylmethyl)amino!-2-oxoethyl!-, benzo b!thien-2-ylmethyl ester,(S) ##STR119##

To a stirred solution of 2-benzothiophenyl p-nitrophenyl carbonate (165mg, 0.5 mmol) in DMF (3 mL) was added (S)-tryptophan-N-methylbenzylamide(154 mg, 0.5 mmol) in DMF (2 mL) and stirring continued overnight atroom temperature. The solvent was removed in vacuo and the residue takenup in ethyl acetate, washed with 1N HCl (aq), NaHCO₃ (aq), brine, dried(MgSO₄), and concentrate in vacuo. The residue was chromatographed onreverse-phase silica (C18) using a gradient of 70% to 90% acetonitrilein water (0.1% TFA) to elute the pure compound (72 mg, 29%); mp 64°-67°C.;

IR (film): 3292, 1713, 1634 cm⁻¹ ;

MS m/e (FAB): 5020.6=M+Na⁺

¹ H NMR (CDCl₃): δ2.50 (2H, m, N-Me); 2.78 (1H, m, N-Me); 3.20 (2H, m,β-CH₂); 3.96 (0.5H, d, 16 Hz, H₃ CH₂ Ph); 4.35 (0.5H, d, 16 Hz, CH₂ Ph);4.41 (0.5H, d, 15 Hz, CH₂ Ph); 4.46 (0.5H, d, 15 Hz, CH₂ Ph); 5.05 (1H,m, α-H); 5.33 (2H, m, ArCH₂ O); 5.78 (1H, m, OCOHN); 6.80-7.83 (15H, m,aromatics); 7.86 (0.5H, s, indole NH); 7.93 (0.5H, s, indole NH);

Analysis calculated for C₂₉ H₂₇ N₃ O₃ S-0.2 H₂ O (C,H,N,S).

We claim:
 1. A compound of formula ##STR120## or a pharmaceuticallyacceptable salt thereof wherein R is phenyl or naphthalene eachunsubstituted, mono-, di-, or trisubstituted byalkyl, hydroxy, alkoxy,NO₂, halogen, NH₂, or CF₃ ; R¹ and R² are each independently hydrogen oralkyl of from 1 to 4 atoms; R and R², when joined by a bond, can form aring; X is ##STR121## wherein R¹¹ is hydrogen or alkyl of from 1 to 3carbon atoms; R³ is hydrogen or (CH₂)_(m) R¹³ where m is an integer offrom 1, to 6 and R¹³ is H, CN, NH₂, N(CH₃)₂, or NHCOCH₃ ; n is aninteger of from 1 to 2; R⁸ is phenyl or naphthalene each unsubstituted,or mono-, di-, or trisubstituted byalkyl, hydroxy, alkoxy, NO₂, halogen,NH₂, or CF₃ ; Y is ##STR122## wherein R⁴ is hydrogen or alkyl of from 1to 3 carbon atoms, --CO₂ --, --COCH₂ --, --CH₂ O--, --CH₂ NH--,--CH═CH--, --CH₂ CH₂ --, --CHOHCH₂ --; R⁵ and R⁷ are each independentlyhydrogen or alkyl of from 1 to 4 carbon atoms; q is an integer of from 0to 1; and R⁶ is phenyl or naphthalene each unsubstituted, or mono-, di-,or trisubstituted byalkyl, hydroxy, alkoxy, NO₂, halogen, NH₂, or CF₃.2. A compound according to claim 1 whereinR is naphthaleneunsubstituted, mono-, di-, trisubstituted byalkyl hydroxy, alkoxy, NO₂,halogen, NH₂, or CF₃ ; R¹ and R² are each independently hydrogen oralkyl of from 1 to 4 atoms; R and R², when joined by a bond, can form aring; X is ##STR123## wherein R¹¹ is hydrogen or alkyl of from 1 to 3carbon atoms; R³ is hydrogen or (CH₂)_(m) R¹³ where m is an integer offrom 1 to 6 and R¹³ is H, CN, NH₂, N(CH₃)₂, or NHCOCH₃ ; n is an integerof from 1 to 2; R⁸ is phenyl or naphthalene each unsubstituted, ormono-, di-, or trisubstituted byalkyl, hydroxy, alkoxy, NO₂, halogen,NH₂, or CF₃ ; Y is ##STR124## wherein R⁴ is hydrogen or alkyl of from 1to 3 carbon atoms, --CO₂ --, --COCH₂ --, --CH₂ O--, --CH₂ NH--,--CH═CH--, --CH₂ CH₂ --, --CHOHCH₂ --; R⁵ and R⁷ are each independentlyhydrogen or alkyl of from 1 to 4 carbon atoms; q is an integer of from 0to 1; and R⁶ is phenyl or naphthalene each unsubstituted, or mono-, di-,or trisubstituted byalkyl, hydroxy, alkoxy, NO₂, halogen, NH₂, or CF₃.3. A compound according to claim 1 whereinR is phenyl or naphthaleneeach unsubstituted, or mono- or disubstituted by alkyl of 1 to 3carbons, methoxy, ethoxy, chlorine, fluorine, NH₂, or CF₃ ; R¹ and R²are each independently selected from hydrogen and methyl; X is##STR125## wherein R¹¹ is hydrogen or methyl; R³ is hydrogen or(CH₂)_(m) R¹³ where m is an integer of from 1 to 6 and R¹³ is H, CN,NH₂, N(CH₃)₂, or NHCOCH₃ ; n is 1; R⁸ is phenyl or naphthyl; Y is##STR126## wherein R⁴ is hydrogen or methyl, --CO₂ --, ##STR127##wherein B is CH, CH₂, D is sulfur, and E is CH, CH₂ ; R⁵ and R⁷ are eachindependently hydrogen or methyl; q is an integer of from 0 to 1, and R⁶is phenyl or substituted phenyl.
 4. A compound according to claim 1whereinR is phenyl unsubstituted, or mono- or disubstituted by alkyl of1 to 3 carbons, methoxy, ethoxy, chlorine, fluorine, NH₂, or CF₃ ; R¹and R² are each independently hydrogen or methyl; X is ##STR128## R³ ishydrogen or methyl; n is 1; Y is ##STR129## R⁵ and R⁷ are eachindependently hydrogen or methyl; q is 1; R⁶ is phenyl or substitutedphenyl.
 5. A pharmaceutical composition comprising an amount of acompound according to claim 1 effective to treat respiratory disordersin a mammal suffering therefrom, and a pharmaceutically acceptablecarrier.
 6. A method for treating respiratory disorders in a mammalcomprising administering a therapeutically effective amount of acompound according to claim
 1. 7. A pharmaceutical compositioncomprising an amount of a compound according to claim 1 effective totreat asthma in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.
 8. A method for treating asthma in a mammalcomprising administering a therapeutically effective amount of acompound according to claim
 1. 9. A pharmaceutical compositioncomprising an amount of a compound according to claim 1 effective totreat inflammation in a mammal suffering therefrom, and apharmaceutically acceptable carrier.
 10. A method for treatinginflammation in a mammal comprising administering a therapeuticallyeffective amount of a compound according to claim
 1. 11. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 effective to treat arthritis in a mammal suffering therefrom,and a pharmaceutically acceptable carrier.
 12. A method for treatingarthritis in a mammal comprising administering a therapeuticallyeffective amount of a compound according to claim
 1. 13. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 effective to treat gastrointestinal disorders in a mammalsuffering therefrom, and a pharmaceutically acceptable carrier.
 14. Amethod for treating gastrointestinal disorders in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto claim
 1. 15. A pharmaceutical composition comprising an amount of acompound according to claim 1 effective to treat ophthalmic diseases ina mammal suffering therefrom, and a pharmaceutically acceptable carrier.16. A method for treating ophthalmic diseases in a mammal comprisingadministering a therapeutically effective amount of a compound accordingto claim
 1. 17. A pharmaceutical composition comprising an amount of acompound according to claim 1 effective to treat allergies in a mammalsuffering therefrom, and a pharmaceutically acceptable carrier.
 18. Amethod for treating allergies in a mammal comprising administering atherapeutically effective amount of a compound according to claim
 1. 19.A pharmaceutical composition comprising an amount of a compoundaccording to claim 1 effective to treat diseases of the central nervoussystem in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.
 20. A method for treating diseases of the centralnervous system in a mammal comprising administering a therapeuticallyeffective amount of a compound according to claim
 1. 21. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 effective to treat migraine in a mammal suffering therefrom,and a pharmaceutically acceptable carrier.
 22. A method for treatingmigraine in a mammal comprising administering a therapeuticallyeffective amount of a compound according to claim
 1. 23. Apharmaceutical composition comprising an amount of a compound accordingto claim 1 effective to treat inflammatory pain or neurogenicinflammation in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.
 24. A method for treating inflammatory pain orneurogenic inflammation in a mammal comprising administration oftherapeutically effective amounts of a compound according to claim 1.25. A pharmaceutical composition comprising an amount of a compoundaccording to claim 1 effective to treat rheumatoid arthritis in a mammalsuffering therefrom, and a pharmaceutically acceptable carrier.
 26. Amethod for treating rheumatoid arthritis in a mammal comprisingadministration of therapeutically effective amounts of a compoundaccording to claim
 1. 27. A pharmaceutical composition comprising anamount of a compound according to claim 1 effective to treatatherosclerosis in a mammal suffering therefrom, and a pharmaceuticallyacceptable carrier.
 28. A method for treating atherosclerosis in amammal comprising administration of therapeutically effective amounts ofa compound according to claim
 1. 29. A pharmaceutical compositioncomprising an amount of a compound according to claim 1 effective totreat tumor cell growth in a mammal suffering therefrom, and apharmaceutically acceptable carrier.
 30. A method for treating tumorcell growth in a mammal comprising administration of therapeuticallyeffective amounts of a compound according to claim
 1. 31. A compoundaccording to claim 1 and selected from:phenylmethyl R-(R*,S*)!-1-(2-naphthalenylmethyl-2-oxo-2- (1-phenylmethyl)amino!ethyl!carbamateand ##STR130##